Pascal Vaudin
email: pascal.vaudin@univ-tours.fr

Corinne Augé

Nathalie Just

Sakina Mhaouty-Kodja

Stéphane Mortaud

Delphine Pillon

When pharmaceutical drugs become environmental pollutants: potential neural effects and underlying mechanisms

Keywords: Pharmaceutical drugs, antibiotics, antidepressants, NSAIDs, neurodevelopment, sexualization, environmental pollutants

Pharmaceutical drugs have become consumer products, with a daily use for some of them. The volume of production and consumption of drugs is such that they have become environmental pollutants. Their transfer to wastewater through urine, feces or rinsing in case of skin use, associated with partial elimination by wastewater treatment plants generalize pollution in the hydrosphere, including drinking water, sediments, soils, the food chain and plants. Here, we review the potential effects of environmental exposure to three classes of pharmaceutical drugs, i.e. antibiotics, antidepressants and non-steroidal anti-inflammatory drugs, on neurodevelopment. Experimental studies analyzing their underlying modes of action including those related to endocrine disruption, and molecular mechanisms including epigenetic modifications are presented. In addition, the contribution of brain imaging to the assessment of adverse effects of these three classes of pharmaceuticals is approached.

Introduction

Human and veterinary medicine uses a large variety of pharmaceutical drugs and their consumption can reach several thousands of tons in some countries [START_REF] Hider-Mlynarz | Trends in analgesic consumption in France over the last 10 years and comparison of patterns across Europe: Trends in analgesic consumption in France and pattern of use in Europe[END_REF][START_REF] Ortiz De García | Consumption and occurrence of pharmaceutical and personal care products in the aquatic environment in Spain[END_REF][START_REF] Van Boeckel | Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data[END_REF]. The hepatic route leads to their partial conjugation (glucuronidation, sulfation, methylation, for elimination) leaving a proportion of pharmacologically active molecule in urine and/or feces during their elimination [START_REF] Kokki | Ketoprofen pharmacokinetics, efficacy, and tolerability in pediatric patients[END_REF][START_REF] Lucas | The Pharmacology of Indomethacin[END_REF][START_REF] Rainsford | Ibuprofen: pharmacology, efficacy and safety[END_REF][START_REF] Verbeeck | Clinical pharmacokinetics of non-steroidal anti-inflammatory drugs[END_REF]. Pharmaceutically active compounds and their metabolites are not completely eliminated by wastewater treatment plants transforming them into environmental pollutants [START_REF] Aemig | Impact assessment of a large panel of organic and inorganic micropollutants released by wastewater treatment plants at the scale of France[END_REF][START_REF] Bisognin | Potential environmental toxicity of sewage effluent with pharmaceuticals[END_REF][START_REF] Chiffre | Occurrence of pharmaceuticals in WWTP effluents and their impact in a karstic rural catchment of Eastern France[END_REF][START_REF] Lonappan | Diclofenac and its transformation products: Environmental occurrence and toxicity -A review[END_REF]. At the worldwide level, pharmaceutical drugs are detectable in surface and ground water with a transfer in sediment and soil showing a global environmental contamination [START_REF] Ahkola | Presence of active pharmaceutical ingredients in the continuum of surface and ground water used in drinking water production[END_REF][START_REF] Der Beek | Pharmaceuticals in the environment-Global occurrences and perspectives: Pharmaceuticals in the global environment[END_REF][START_REF] Awad | Veterinary antibiotics contamination in water, sediment, and soil near a swine manure composting facility[END_REF][START_REF] Besse | Human pharmaceuticals in surface waters[END_REF][START_REF] Charuaud | Veterinary pharmaceutical residues from natural water to tap water: Sales, occurrence and fate[END_REF][START_REF] Desbiolles | Occurrence and ecotoxicological assessment of pharmaceuticals: Is there a risk for the Mediterranean aquatic environment?[END_REF][START_REF] Ortiz De García | Consumption and occurrence of pharmaceutical and personal care products in the aquatic environment in Spain[END_REF][START_REF] Wang | Implementing ecopharmacovigilance (EPV) from a pharmacy perspective: A focus on non-steroidal anti-inflammatory drugs[END_REF]. In many species, brain development and function are dependent on internal factors including steroid and thyroid hormones [START_REF] Coumailleau | Aromatase, estrogen receptors and brain development in fish and amphibians[END_REF][START_REF] Duarte-Guterman | Regulation of thyroid hormone-, oestrogen-and androgen-related genes by triiodothyronine in the brain of Silurana tropicalis[END_REF]. In mammals, neurogenesis, cell migration and neuro-glial differentiation in the cerebral cortex, hippocampus and hypothalamus are mediated by sex steroids and thyroid hormones [START_REF] Adhya | Understanding the role of steroids in typical and atypical brain development: Advantages of using a "brain in a dish" approach[END_REF][START_REF] Parent | Early developmental actions of endocrine disruptors on the hypothalamus, hippocampus, and cerebral cortex[END_REF][START_REF] Zoeller | Thyroid hormone, brain development, and the environment[END_REF]. During development, the sexual differentiation of the brain is regulated by sex steroids through the masculinization of several brain areas including the preoptic area (POA), a sexually dimorphic region of the hypothalamus regulating sexual behavior in male and maternal behavior in female (Schwarz and McCarthy, 2008a). At the adult stage, sex steroids play a crucial role in reproductive function since they trigger the puberty and control the neuro-glial Gonadotropin-Releasing Hormone (GnRH) and kisspeptin networks [START_REF] Delemarre | Inducing puberty[END_REF][START_REF] Nestor | Regulation of GnRH pulsatility in ewes[END_REF][START_REF] Vigil | Endocrine Modulation of the Adolescent Brain: A Review[END_REF]. This dependence on steroids and thyroid hormones makes the brain a target for molecules with endocrine disrupting activity during perinatal stage and adulthood. In addition, thyroid hormones also target the brain through their involvement in maturation phases. In particular, they have a crucial role for the myelination and myelin turnover [START_REF] Calzà | Role of the Thyroid System in Myelination and Neural Connectivity[END_REF]. Moreover, recent studies show that thyroid hormones play an important role in microglial development [START_REF] Rousseau | Facilitation of microglial motility by thyroid hormones requires the presence of neurons in cell culture: A distinctive feature of the brainstem versus the cortex[END_REF].

Many of the pharmaceutical drugs, which are now considered also as environmental pollutants, exert their therapeutic action by interacting with the endocrine system and for many of them, with neural cells. The benefits of pharmaceutical drugs as therapeutic agents is no longer to demonstrate. These molecules undergo both pre-clinical and clinical trial phases before their marketing, consisting in toxicologic assessments to evaluate potential risks (carcinogenicity, genotoxicity, reproductive toxicity…) according to the guidelines proposed by the International Council on Harmonization or ICH [START_REF] Goineau | Overview of safety pharmacology[END_REF]; "https://www.ich.org/," n.d.) for human pharmaceuticals and VICH for veterinarian compounds (https://vichsec.org/en/). The adverse impact of candidate drugs on the central nervous system (CNS) are evaluated during the pre-clinical phase in accordance with three guidelines: i) the guideline S7A (safety pharmacology studies) with behavioral tests after a single injection of the pharmaceutical candidate in adult animals, ii) the Pre-and Post-Natal development (PPND) study of the guideline S5 (R3) (reproductive toxicology) with behavioral tests after developmental exposure, from E6 to PN21 in rat (from the 6 th day of embryonic (E) development to the 21 st Post-Natal (PN) day) and iii) the guideline S11 or Juvenile Animal Study (JAS) for the assessment of potential toxic effects on neonate, infant, child and/or adolescent with behavioral tests, learning and memory tests and neuro-histopathology evaluations. These regulatory assessments do not evaluate adverse effects of pharmaceutical drugs at neuroanatomical, cellular or molecular level [START_REF] Barrow | Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2016 and 2017[END_REF]; "https://www.ich.org/page/safety-guidelines," n.d.). Only very few studies reported the impact of these candidate molecules as environmental pollutants. Nevertheless, an environmental risk assessment has to accompany an application for a marketing authorization for a pharmaceutical. It consists in the determination of the Predicted Environmental Concentration (PEC) of the drug substance in surface water and the evaluation of adverse effects (if the PEC exceeds 0.01µg/L) on algae, Daphnia and fish (https://www.ema.europa.eu/en/documents/scientific-guideline/guidelineenvironmental-risk-assessment-medicinal-products-human-use-first-version_en.pdf). The aim of this article is to review the potential adverse effects of three categories of pharmaceutical environmental pollutants: the antibiotics, the antidepressants and the anti-inflammatory drugs, on the development of the central nervous system (CNS) in mammals. These three categories of pharmaceuticals were chosen according to the following criteria: i) they are largely consumed, ii) they are quasi-systematically listed in dosing studies reported in the scientific literature and iii) they are huge environmental contaminants and notably for the hydrosphere. The mechanisms underlying the potential endocrine disrupting effects of these pharmaceuticals will be discussed. Since a delay exists between the exposition during development and the manifestation of the adverse effects, at adult stage, we will expose the implication of epigenetic modifications that may account for such delayed effects. Finally, we will briefly introduce the potential of neuroimaging techniques for measuring and following the endocrine changes induced by pharmaceutical agents.

Neural effects of exposure to antibiotics

Antibiotics are widely used in human medicine and most importantly in veterinary medicine and agriculture [START_REF] Jechalke | Fate and effects of veterinary antibiotics in soil[END_REF][START_REF] Machowska | Drivers of Irrational Use of Antibiotics in Europe[END_REF]. Therefore, their emission in the environment is mainly due to human sources (hospital waste, and wastewater treatment plant…), and to a larger extent to agricultural uses as therapeutic molecules but also as promoters of animal growth [START_REF] Puckowski | Bioaccumulation and analytics of pharmaceutical residues in the environment: A review[END_REF]. Previous research highlighted the worldwide presence of antibiotics, with regional differences among the five analyzed regions across Eastern and Western Europe, Asia, Africa and America (aus der [START_REF] Der Beek | Pharmaceuticals in the environment-Global occurrences and perspectives: Pharmaceuticals in the global environment[END_REF]. Studies monitoring the occurrence of pharmaceutical substances detected antibiotics in wastewater treatment plants, surface water, groundwater sediments and aquatic species including invertebrates and vertebrates [START_REF] Ahkola | Presence of active pharmaceutical ingredients in the continuum of surface and ground water used in drinking water production[END_REF][START_REF] Awad | Veterinary antibiotics contamination in water, sediment, and soil near a swine manure composting facility[END_REF][START_REF] Charuaud | Veterinary pharmaceutical residues from natural water to tap water: Sales, occurrence and fate[END_REF][START_REF] Chiffre | Occurrence of pharmaceuticals in WWTP effluents and their impact in a karstic rural catchment of Eastern France[END_REF][START_REF] Guo | Prioritizing pharmaceuticals based on environmental risks in the aquatic environment in China[END_REF][START_REF] Ortiz De García | Consumption and occurrence of pharmaceutical and personal care products in the aquatic environment in Spain[END_REF][START_REF] Wee | Tap water contamination: Multiclass endocrine disrupting compounds in different housing types in an urban settlement[END_REF][START_REF] Xie | Bioaccumulation and trophic transfer of pharmaceuticals in food webs from a large freshwater lake[END_REF]. The resulting measured concentrations in the environment vary from nanograms or micrograms to milligrams, with seasonal variations and higher concentrations in winter than in summer [START_REF] Awad | Veterinary antibiotics contamination in water, sediment, and soil near a swine manure composting facility[END_REF][START_REF] Kot-Wasik | Occurrence and seasonal variations of 25 pharmaceutical residues in wastewater and drinking water treatment plants[END_REF]. In mammals, the neural effects of antibiotics were mainly studied in the context of therapeutic use. Encephalopathy, optic neuropathy, seizures and peripheral neuropathy are some examples of undesirable neurotoxic side effects associated with their use [START_REF] Koppel | Seizures in the critically ill: the role of imipenem[END_REF][START_REF] Lamoth | Reassessment of recommended imipenem doses in febrile neutropenic patients with hematological malignancies[END_REF][START_REF] Weinstein | Neurotoxicity in patients treated with intravenous polymyxin B: Two case reports[END_REF]. It has been shown, in particular, that following therapeutic use certain antibiotics induced neurotoxic effects via the disruption of neurotransmitter release or the functional alteration of neurotransmitter receptors, the increase in glutamate levels, the release of cytokines in the brain as well as the modification of blood-brain barrier permeability [START_REF] Chow | Neurotoxicity induced by beta-lactam antibiotics: from bench to bedside[END_REF][START_REF] Fiekers | Comparative effects of clindamycin and lincomycin on end-plate currents and quantal content at the neuromuscular junction[END_REF][START_REF] Sugimoto | Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins[END_REF]. Fetal, postnatal and early childhood are critical periods for neural development. The disruption of the systems involved in brain homeostasis during these early periods of neurodevelopment can have long-term consequences. Future studies are needed to determine whether environmental exposure to antibiotics directly affects brain development or whether microbiome molecules that travel to the brain disrupt gene activity and cause cognitive deficits. In humans, a longitudinal cohort study showed that 70% of European children who received antibiotics in early life, but not during pregnancy, presented higher ratings of social difficulties, attention deficit hyperactivity disorder and depression symptoms at a later age compared to non-exposed children [START_REF] Slykerman | Antibiotics in the first year of life and subsequent neurocognitive outcomes[END_REF]. It was shown in several mammalian studies that administration of high doses of antibiotics during critical periods of development induced long-term effects on brain and behavior by acting directly on the nervous system or indirectly through microbiota modifications (reviewed by [START_REF] Champagne-Jorgensen | Antibiotics and the nervous system: More than just the microbes?[END_REF]. In rodents, pre-breeding and/or gestational exposure to one antibiotic (1% succinylsulfathiazole in diet) or to an antibiotic cocktail (5 mg/ml neomycin, 5 mg/ml bacitracin and 1.25 μg/ml pimaricin in drinking water) elicited changes in social and emotional behaviors [START_REF] Degroote | Maternal gut and fetal brain connection: Increased anxiety and reduced social interactions in Wistar rat offspring following peri-conceptional antibiotic exposure[END_REF][START_REF] Tochitani | Administration of Non-Absorbable Antibiotics to Pregnant Mice to Perturb the Maternal Gut Microbiota Is Associated with Alterations in Offspring Behavior[END_REF]. In agreement with this study, it was recently shown that perinatal exposure of mice to a relatively low-dose of penicillin (31 mg/kg/d) induced long-term modifications in the cortical cytokine expression, blood-brain barrier integrity, and behavior [START_REF] Leclercq | Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior[END_REF]. In particular, antibiotic-treated offspring exhibited impaired anxiety-like, social and aggressive behaviors. The cellular and molecular mechanisms reported for antibiotics are briefly summarized here. Several scientific studies using electrophysiology have shown that some of these antibiotics interfere with the glutamatergic and / or gabaergic systems. These interactions had been demonstrated in the past for all quinolone antibiotics, such as norfloxacin and ciprofloxacin, which inhibited the specific binding of ligands to GABAA and ionotropic glutamate receptors in a concentration-dependent manner, with an IC20 of 220-930 µM and 70-480 µM, respectively, in mammalian cells [START_REF] Dodd | Neurochemical Studies on Quinolone Antibiotics: Effects on Glutamate, GABA and Adenosine Systems in Mammalian CNS[END_REF][START_REF] Halliwel | A patch clamp study of the effects of ciprofloxacin and biphenyl acetic acid on rat hippocampal neurone GABAA and lonotropic glutamate receptors[END_REF]. Given the importance of the gabaergic and glutamatergic systems in various processes of neurogenesis, this raises the question of the risk of chronic exposure to these antibiotics during development, due to environmental contamination. Otherwise, the neurotoxic effects of some quinolones in combination with certain non-steroidal anti-inflammatory drugs enhanced the inhibitory potency of ciprofloxacin by approximately 3000-fold (100 µM versus 0.03 µM) as previously reported [START_REF] Halliwel | A patch clamp study of the effects of ciprofloxacin and biphenyl acetic acid on rat hippocampal neurone GABAA and lonotropic glutamate receptors[END_REF]. Another cellular mechanism that was widely reported for the neural effects of antibiotics involves microglia. It has been established for several years that certain antibiotics, such as tetracyclines or minocycline, have an inhibitory action on microglial cells, the immune cells of the central nervous system [START_REF] Schmidtner | Minocycline alters behavior, microglia and the gut microbiome in a trait-anxiety-dependent manner[END_REF][START_REF] Scott | Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration[END_REF][START_REF] Tikka | Minocycline, a Tetracycline Derivative, Is Neuroprotective against Excitotoxicity by Inhibiting Activation and Proliferation of Microglia[END_REF]. Recent studies demonstrated that microglial activation is not only a hall-mark of neuroinflammation, but plays important roles during brain development. Inhibition of microglial activation by minocycline was shown to induce extensive neuronal cell death and impair neurogenesis in the subventricular zone (SVZ) and synaptic pruning in the early postnatal and adolescent rodent brain, respectively [START_REF] Inta | Microglia Activation and Schizophrenia: Lessons From the Effects of Minocycline on Postnatal Neurogenesis, Neuronal Survival and Synaptic Pruning[END_REF]. These deleterious effects contrast with the neuroprotective actions of minocycline at adult stages [START_REF] Arnoux | Paradoxical effects of minocycline in the developing mouse somatosensory cortex: Effects of Minocycline in the Developing Cortex[END_REF][START_REF] Liu | Interaction of erythromycin and ketoconazole on the neurological, biochemical and behavioral responses in crucian carp[END_REF][START_REF] Ueno | Layer V cortical neurons require microglial support for survival during postnatal development[END_REF]. It has been reported in mammals that catalase and glutathione s-transferase are also modulated by tetracycline in some organs, including the brain [START_REF] Satpute | Effect of resveratrol and tetracycline on the subacute paraquat toxicity in mice[END_REF][START_REF] Turkan | Toxicological effects of some antiparasitic drugs on equine liver glutathione S-Transferase enzyme activity[END_REF]. It is of particular interest to note that these two enzymes are important in microglial cells to promote pro-inflammatory astro-microglia communication [START_REF] Kano | Glutathione S -transferases promote proinflammatory astrocyte-microglia communication during brain inflammation[END_REF]. Therefore, changes in microglial function could trigger important brain disturbance if exposure to antibiotics occurs during developmental periods. Neural effects of exposure to antibiotics were also reported in aquatic models, which with other wild life represent good sentinels for the environmental contamination (Animals as Sentinels of Environmental Health Hazards, 1991). Exposure of zebrafish to norfloxacin (600, 900 and 1200 mg/L) affected not only the hatching rate, increased mortality and malformation rate of the embryos, but also inhibited the expression of glial (Glial fibrillary acidic protein or GFAP), stem cell (sex determining region Y-box 2 or sox2) and mature neuronal (enolase 2) markers [START_REF] Xi | Effects of norfloxacin exposure on neurodevelopment of zebrafish (Danio rerio) embryos[END_REF]. In addition, exposure to norfloxacin induced cell apoptosis in the brain of zebrafish embryos as evidenced by measurement of caspase 3 activity and expression ratio of Bcl-2-associated X (Bax) to B-cell lymphoma 2 (Bcl2). The apoptotic phenotype was rescued by administration of MK-801, a noncompetitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, suggesting that the activation of NMDA receptors mediated the developmental neurotoxicity of this antibiotic. Another study focused on acute exposure effects of tetracycline (5, 50 and 500 ng/L), an antibiotic subclass representing the second highest frequency of detection in environmental matrices, in the freshwater fish Gambusi holbrooki [START_REF] Nunes | Acute Effects of Tetracycline Exposure in the Freshwater Fish Gambusia holbrooki: Antioxidant Effects, Neurotoxicity and Histological Alterations[END_REF]. The results suggested the existence of a cause-and-effect relationship between tetracycline exposure and antioxidant effects, neurotoxicity, histological alterations and glutathion-S-transferase, catalase and acetylcholinesterase enzymatic activities as described above in mammals. The potential effects of antibiotics were also studied in the context of combined exposure with other environmentally detected pharmaceuticals. [START_REF] Liu | Interaction of erythromycin and ketoconazole on the neurological, biochemical and behavioral responses in crucian carp[END_REF] showed that combined exposure of Crucian carp to an antibiotic, erythromycin, at 2 μg/L and an anti-fungal molecule, ketoconazole, at 0.2, 2 or 20 μg/L inhibited acetylcholine esterase activity and swimming behavior and enhanced shoaling. Exposure of fish, Astyanax bimaculatus, to sewage effluents added with five pharmaceuticals including four antibiotics (ciprofloxacin at 11.44 μg/L, oxytetracycline at 7.93 μg/L, sulfamethoxazole at 188.69 μg/L, trimethoprim at 30.65 μg/L) and paracetamol at 151.17 μg/L increased glutathione-S-transferase activity in the brain [START_REF] Bisognin | Potential environmental toxicity of sewage effluent with pharmaceuticals[END_REF]. Whether antibiotics found in the environment trigger neural adverse effects for human health and environment through endocrine mode(s) of action still needs a thorough investigation, in particular at environmental doses. However, some evidences in aquatic animals point out a possible alteration of neuroendocrine systems. Chronic exposure of Japanese medaka (Oryzias latipes) for 120 days to cefadroxil at 84.8 µg/L and cefradine since 73.9 µg/L impaired growth and reproduction [START_REF] Kim | Effects of chronic exposure to cefadroxil and cefradine on Daphnia magna and Oryzias latipes[END_REF]. These effects were associated with altered expression levels of gnrh1, gnrh2, estrogen receptors (esr1, esr2), and cyp19b in the brain [START_REF] Kim | Effects of chronic exposure to cefadroxil and cefradine on Daphnia magna and Oryzias latipes[END_REF]. Modifications in the pituitary expression of gnrh1r and gnrh2r encoding GnRH receptors and in estradiol levels were also observed [START_REF] Kim | Effects of chronic exposure to cefadroxil and cefradine on Daphnia magna and Oryzias latipes[END_REF]. In a previous study, the same group showed that chronic exposure of Japanese medaka to lincomycin at 0.42 mg/L significantly reduced juvenile survival at 30 day post-hatch [START_REF] Kim | Effect of chronic exposure to acetaminophen and lincomycin on Japanese medaka (Oryzias latipes) and freshwater cladocerans Daphnia magna and Moina macrocopa, and potential mechanisms of endocrine disruption[END_REF].

Interestingly, exposure to lincomycin also increased vitellogenin levels in male fish at 90-day post-hatch. In the same study, exposure of human adrenal cells to lincomycin also altered steroidogenesis and increased estradiol concentrations. In accordance with these data, another antibiotic, ciprofloxacin has been previously reported to inhibit the activity of cytochrome P450, a key enzyme in hormone synthesis, in rat and human [START_REF] Granfors | Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2?mediated presystemic metabolism[END_REF][START_REF] Mclellan | Fluoroquinolone antibiotics inhibit cytochrome P450-mediated microsomal drug metabolism in rat and human[END_REF]. Besides these studies reporting alterations in the gonadotropic axis and/or in steroidogenesis, thyroid disruption was also observed in a study addressing long-term exposure of Zebrafish embryos to environmentally relevant concentrations of oxytetracycline (1000 or 5000 ng/L) from 2 h to 120 d post-fertilization [START_REF] Yu | Low-dose effects on thyroid disruption in zebrafish by long-term exposure to oxytetracycline[END_REF]. In particular, exposure to oxytetracycline increased triiodothyronin concentrations, reduced levels of thyroid stimulating hormone, and affected growth and development of Zebrafish. From these studies, it appears that relatively low doses of antibiotics can exhibit endocrine modes of action in aquatic models, through impairment of the gonadotropic or the thyroid axes. This raises the question of the potential adverse effect on the nervous system, given the importance of thyroid and sex hormones in neural processes during critical periods of development.

Effects of antidepressants on CNS development

Numerous psychiatric pharmaceuticals are widely prescribed to treat mental illnesses such as depression, psychosis, anxiety, epilepsy or mood disorders. Therefore antidepressants constitute one of the most commonly prescribed drugs in developed countries (France, [START_REF] Aemig | Impact assessment of a large panel of organic and inorganic micropollutants released by wastewater treatment plants at the scale of France[END_REF]Spain, Ortiz de García et al., 2013;USA, Pratt et al., 2017;reviewed by Castillo-Zacarías et al., 2021). The growing consumption of antidepressants is associated to a growing occurrence of these drugs in urban waters as well as in rivers and oceans [START_REF] Der Beek | Pharmaceuticals in the environment-Global occurrences and perspectives: Pharmaceuticals in the global environment[END_REF][START_REF] Martin | Impact of the widespread pharmaceutical pollutant fluoxetine on behaviour and sperm traits in a freshwater fish[END_REF][START_REF] Mole | Global scanning of selective serotonin reuptake inhibitors: occurrence, wastewater treatment and hazards in aquatic systems[END_REF][START_REF] Saaristo | Behavioural effects of psychoactive pharmaceutical exposure on European perch (Perca fluviatilis) in a multi-stressor environment[END_REF], leading to an emerging environmental contamination by antidepressants. Antidepressants act directly on brain's biochemistry by modifying neurotransmitter metabolism. Various classes of antidepressants implicate different mechanisms of action within the CNS, regulating notably the serotonin neurotrophic effects. Each class is identified according to its mechanism of action on neurotransmitters: the selective serotonin reuptake inhibitors (SSRIs), which are the most widely prescribed [START_REF] Kulikov | Interplay between the key proteins of serotonin system in SSRI antidepressants efficacy[END_REF]; the serotonin and norepinephrine reuptake inhibitors (SNRIs); the serotonin modulators and stimulators (SMSs); the serotonin antagonists and reuptake inhibitors (SARIs); the noradrenergic and selective serotoninergic antidepressants (NaSSAs); the norepinephrine reuptake inhibitors (NeRIs); the serotonin, norepinephrine and dopamine reuptake inhibitors (SNDRIs) or triple reuptake inhibitors (TRIs); and the melatonin and serotonin agonists (MaSAs) [START_REF] Fitzgerald | In vivo electrophysiological recordings of the effects of antidepressant drugs[END_REF]. SSRIs are mainly prescribed for treating major depressive disorder, and particularly perinatal depression [START_REF] Latendresse | Selective Serotonin Reuptake Inhibitors as First-Line Antidepressant Therapy for Perinatal Depression[END_REF]. Among them, fluoxetine (Prozac ® ) is metabolized by cytochrome P-450 isoenzymes to norfluoxetine, which retain the pharmacological activity [START_REF] Mandrioli | Fluoxetine Metabolism and Pharmacological Interactions: The Role of Cytochrome P450[END_REF]. This active metabolite is eliminated in the urine and then disseminates into wastewaters. Fluoxetine and norfluoxetine are widely detected into various environmental compartments such as surface, ground, marine and drinking waters, soils and sediments in the range of ng/L to mg/L [START_REF] Biel-Maeso | Monitoring the occurrence of pharmaceuticals in soils irrigated with reclaimed wastewater[END_REF]. In the United Kingdom, fluoxetine can be detected in drinking water at low concentrations (0.27 ng/L; [START_REF] Peng | The detection of drugs of abuse and pharmaceuticals in drinking water using solid-phase extraction and liquid chromatography-mass spectrometry[END_REF]. In this review, fluoxetine is taken as an example of SSRIs antidepressant that constitutes an environmental pollutant.

According to a report from the Organization for Economic Cooperation and Development (OECD) on pharmaceuticals consumption in 2019 (OECD iLibrary), the consumption of antidepressant drugs doubled in OECD countries between 2000 and 2017. Such an increase in human consumption generated an amplification in environmental contamination (reviewed by [START_REF] Castillo-Zacarías | Antidepressant drugs as emerging contaminants: Occurrence in urban and non-urban waters and analytical methods for their detection[END_REF]. Therefore antidepressants constitute emerging environmental pollutants. Regarding the wide dissemination of antidepressants in the environment, numerous studies demonstrated deleterious biological effects on aquatic wildlife ecosystems due to antidepressant contamination in the environment (reviewed by [START_REF] Sehonova | Effects of waterborne antidepressants on non-target animals living in the aquatic environment: A review[END_REF]. Antidepressant dissemination in rivers, estuaries and coastal waters exposes aquatic organisms like fishes, amphibians or mollusks, leading to alterations in essential physiological and behavioral processes through neurological and neuroendocrine effects. For example, in eastern mosquitofish (Gambusia holbrooki), fluoxetine exposure at environmental doses alters antipredator and anxiety-related behaviors [START_REF] Martin | Impact of the widespread pharmaceutical pollutant fluoxetine on behaviour and sperm traits in a freshwater fish[END_REF][START_REF] Martin | The psychoactive pollutant fluoxetine compromises antipredator behaviour in fish[END_REF], as well as reproductive behaviors such as courtship and sexual partners interactions [START_REF] Martin | Impact of the widespread pharmaceutical pollutant fluoxetine on behaviour and sperm traits in a freshwater fish[END_REF] or copulatory behavior [START_REF] Bertram | The antidepressant fluoxetine alters mechanisms of preand post-copulatory sexual selection in the eastern mosquitofish (Gambusia holbrooki)[END_REF][START_REF] Fursdon | The pharmaceutical pollutant fluoxetine alters reproductive behaviour in a fish independent of predation risk[END_REF].

In the meagre (Argyrosomus regius), [START_REF] Duarte | Depressed, hypertense and sore: Long-term effects of fluoxetine, propranolol and diclofenac exposure in a top predator fish[END_REF] demonstrated alterations in fish growth, oxidative stress, detoxification mechanisms and lipid peroxidation in the liver [START_REF] Duarte | Depressed, hypertense and sore: Long-term effects of fluoxetine, propranolol and diclofenac exposure in a top predator fish[END_REF]. Such results suggest an endocrine disruption mode of action implicating alterations within the hypothalamic-pituitary-adrenal (HPA) axis, the gonadotropic axis or the thyroid hormones regulation. Beyond such effects disturbing aquatic wildlife ecosystems, antidepressant metabolites concentrate in brain and liver tissues [START_REF] David | Concentrating mixtures of neuroactive pharmaceuticals and altered neurotransmitter levels in the brain of fish exposed to a wastewater effluent[END_REF][START_REF] Pan | Tissue bioconcentration and effects of fluoxetine in zebrafish (Danio rerio) and red crucian cap (Carassius auratus) after short-term and long-term exposure[END_REF], as well as in plasma, of fishes consumed by humans [START_REF] Sims | Pharmaceutical uptake kinetics in rainbow trout: In situ bioaccumulation in an effluent-dominated river influenced by snowmelt[END_REF]. Therefore, either through direct effects via drinking water or through indirect effects via aquatic food, environmental contamination by antidepressants may constitute a risk for human health. Antidepressant drugs such as fluoxetine are commonly prescribed in women for treating major depressive disorder during pregnancy and/or postpartum depression. As these drugs cross the placental barrier [START_REF] Arumugasaamy | Model Placental Barrier Phenotypic Response to Fluoxetine and Sertraline: A Comparative Study[END_REF][START_REF] Hendrick | Placental Passage of Antidepressant Medications[END_REF] and diffuse in breast milk [START_REF] Schoretsanitis | The impact of pregnancy on the pharmacokinetics of antidepressants: a systematic critical review and meta-analysis[END_REF][START_REF] Schoretsanitis | Antidepressants in breast milk; comparative analysis of excretion ratios[END_REF], and because of their action on neurotransmitter metabolism, antidepressants are expected to affect the developing fetal and postnatal brain of respectively fetuses and newborns. Then antidepressants may constitute a risk for human health as their potential disrupting effects during embryonic and postnatal brain development may alter development, growth and regulation of neural systems, as well as neural plasticity, with long-term consequences.

In rodents, developmental exposure to antidepressants during prenatal life and/or lactation has been demonstrated to induce long-term endocrine, behavioral and neural alterations. Most of the results are relatives to the control of the HPA axis. In mice, developmental fluoxetine exposure alters endocrine and behavioral response to stress in adult female and male progeny [START_REF] Avitsur | Prenatal fluoxetine modifies the behavioral and hormonal responses to stress in male mice: role for glucocorticoid insensitivity[END_REF][START_REF] Avitsur | Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance[END_REF]. Indeed prenatal fluoxetine exposure disrupts the negative feedback control of the HPA axis response to stress and reduces anxiety-and depressive-like behaviors at adulthood, that could be due to a glucocorticoid insensitivity. In rats, postnatal fluoxetine exposure up to weaning induces in male offspring only, at adult stage, an increase in anxiety-like behavior and impairments in HPA axis negative feedback [START_REF] Gobinath | Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis[END_REF]. These impairments are associated with sexually dimorphic adult hippocampal neurogenesis alterations, since hippocampal neurogenesis is amplified in adult males after preweaning fluoxetine exposure and reduced in adult females. Otherwise, perinatal fluoxetine has been shown, in male rats, to decrease corticosterone levels, to increase both serotonin levels in the hippocampus and pre-synaptic density in the dentate gyrus [START_REF] Gemmel | Perinatal fluoxetine effects on social play, the HPA system, and hippocampal plasticity in pre-adolescent male and female rats: Interactions with pre-gestational maternal stress[END_REF], and to induce sexually differentiated effects on hippocampal neurogenesis and glucocorticoid receptor density [START_REF] Gemmel | Perinatal fluoxetine has enduring sexually differentiated effects on neurobehavioral outcomes related to social behaviors[END_REF]. Moreover, on prenatally stressed progeny, developmental fluoxetine exposure modifies the dopaminergic system in the hippocampus and decreases monoamine levels [START_REF] Gemmel | Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning: Developmental SSRIs Affect PFC and Hippocampus[END_REF]. Decreases in hippocampal BDNF IV and its receptor TrkB mRNA expression after developmental fluoxetine exposure constitute other molecular processes that may be implicated in long-term programming effects on brain and behavior [START_REF] Boulle | Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring[END_REF]. Other studies reported fluoxetine-induced alterations within the reproductive function. In male mice, fluoxetine exposure during fetal development and lactation reduces at adulthood sexual motivation [START_REF] Gouvêa | Maternal exposure to the antidepressant fluoxetine impairs sexual motivation in adult male mice[END_REF]. In rats, developmental fluoxetine exposure induces in adult male sexual behavior impairments [START_REF] Rayen | Developmental fluoxetine exposure and prenatal stress alter sexual differentiation of the brain and reproductive behavior in male rat offspring[END_REF]. Moreover, it decreases the area of the sexually dimorphic nucleus of the preoptic area (SDN-POA), implicated in rodents in the control of sexual behavior. Comparable to fluoxetine, sertraline, a frequently prescribed SSRI, has been demonstrated to modify as well neuroendocrine and behavioral parameters in progeny of maternal exposure in rodents. In rats, [START_REF] Kott | Developmental outcomes after gestational antidepressant treatment with sertraline and its discontinuation in an animal model of maternal depression[END_REF] described alterations in HPA axis secretions, anxiety behavior and cognition, with sex-specific effects in the adult offspring [START_REF] Kott | Developmental outcomes after gestational antidepressant treatment with sertraline and its discontinuation in an animal model of maternal depression[END_REF]. Moreover, sertraline developmental exposure throughout gestation modifies permanently in adult mice the levels of serotonin receptors and transporters mRNAs in the cerebral cortex [START_REF] Meyer | Perinatal SSRI exposure permanently alters cerebral serotonin receptor mRNA in mice but does not impact adult behaviors[END_REF]. Altogether, these results demonstrate long-term endocrine and behavioral, as well as neural, effects after prenatal and perinatal SSRIs exposure. The neural effects are suspected to be involved in endocrine and behavioral alterations, as some remodeling of neural circuits in early life are able to modulate behavioral responses at adulthood. If literature reporting endocrine, behavioral and neural effects induced by developmental exposure to pharmacological SSRI doses is significant, in contrast literature related to human risk constituted by antidepressants exposure at environmental doses during pre-and peri-natal development is poorly documented. We can notice that, through in vitro and in silico approaches using differentiated human neuroblastoma cells treated with a mixture of psychoactive pharmaceuticals including fluoxetine at environmentally relevant concentrations, [START_REF] Kaushik | Psychoactive pharmaceuticals at environmental concentrations induce in vitro gene expression associated with neurological disorders[END_REF][START_REF] Kaushik | Dysregulation of autismassociated synaptic proteins by psychoactive pharmaceuticals at environmental concentrations[END_REF] identified alterations in neuronal gene expression associated with neurological disorders such as Autism Spectrum Disorders (ASD), Alzheimer's disease and schizophrenia. Among the genes exhibiting expression alterations, several genes coding synaptic proteins associated with ASD are affected [START_REF] Kaushik | Dysregulation of autismassociated synaptic proteins by psychoactive pharmaceuticals at environmental concentrations[END_REF][START_REF] Kaushik | Psychoactive pharmaceuticals at environmental concentrations induce in vitro gene expression associated with neurological disorders[END_REF]. Finally, it can be mentioned that some indirect effects may be suspected, implicating the gut microbiota. Gut microbial metabolites participate to homeostasis and development. If maternal SSRIs treatment modifies maternal microbiota, the progeny central nervous system may be the trigger of alterations with long-term consequences [START_REF] Ramsteijn | Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression[END_REF]. Therefore more studies using environmentally relevant doses are needed to evaluate the risk for human health of antidepressants environmental contamination. Technological progress is aiming to remove pharmaceuticals from sewage (reviewed by [START_REF] De Oliveira | Pharmaceuticals residues and xenobiotics contaminants: Occurrence, analytical techniques and sustainable alternatives for wastewater treatment[END_REF]. If, over last years, such progress has improved, however, such as for most of pharmaceuticals, wastewater treatments remain only partially efficient in removing antidepressant molecules. Considering the diversity of pharmaceuticals detected in various environmental compartments, notably antidepressant molecules, triggering the CNS and neurotransmitter metabolism, cocktail effects have to be defined.

NSAIDs and neurodevelopment

Nonsteroidal anti-inflammatory drugs (NSAIDs) are pharmaceuticals that reduce pain, decrease fever and inflammation. Diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen and paracetamol (or acetaminophen) are the most common, they are free sold in numerous countries [START_REF] Rayen | Developmental fluoxetine exposure and prenatal stress alter sexual differentiation of the brain and reproductive behavior in male rat offspring[END_REF]. In 2010's approximatively 250 000 kg of ibuprofen were consumed in Germany, France, Spain; 1 065 000 kg and 3 300 000 kg of paracetamol were consumed respectively in Spain and France [START_REF] Chiffre | Occurrence of pharmaceuticals in WWTP effluents and their impact in a karstic rural catchment of Eastern France[END_REF][START_REF] Ortiz De García | Consumption and occurrence of pharmaceutical and personal care products in the aquatic environment in Spain[END_REF]. Pharmacokinetic studies show that NSAIDs are excreted via urine and feces in conjugated and free forms [START_REF] Lucas | The Pharmacology of Indomethacin[END_REF][START_REF] Rainsford | Ibuprofen: pharmacology, efficacy and safety[END_REF][START_REF] Small | Diclofenac sodium[END_REF]. These metabolized and non-metabolized NSAIDs forms in addition to creams, gel and patch are not totally eliminated by wastewater treatment plants [START_REF] Wang | Implementing ecopharmacovigilance (EPV) from a pharmacy perspective: A focus on non-steroidal anti-inflammatory drugs[END_REF]. Therefore, NSAIDs are frequently dosed in the hydrosphere, sediments and soil showing a general contamination [START_REF] Amalric | Suivi des résidus de substances pharmaceutiques dans les systèmes aquatiques du bassin Loire-Bretagne[END_REF][START_REF] Der Beek | Pharmaceuticals in the environment-Global occurrences and perspectives: Pharmaceuticals in the global environment[END_REF][START_REF] Ortiz De García | Consumption and occurrence of pharmaceutical and personal care products in the aquatic environment in Spain[END_REF]. The consequences of this general pollution is the contamination of the animal trophic chain, from phytoplankton to predators [START_REF] Bean | Pharmaceuticals in water, fish and osprey nestlings in Delaware River and Bay[END_REF][START_REF] Xie | Bioaccumulation and trophic transfer of pharmaceuticals in food webs from a large freshwater lake[END_REF], vegetables [START_REF] Wu | Comparative uptake and translocation of pharmaceutical and personal care products (PPCPs) by common vegetables[END_REF] and drinking water. Indeed, contamination of drinking water is reported in several studies in multiple areas with maximum concentrations of 1 350 ng/L for ibuprofen in United States, 166 ng/L for ketoprofen and 114 ng/L for diclofenac in Poland and 210 ng/L for paracetamol in France [START_REF] Caban | Determination of pharmaceutical residues in drinking water in Poland using a new SPE-GC-MS(SIM) method based on Speedisk extraction disks and DIMETRIS derivatization[END_REF][START_REF] Kot-Wasik | Occurrence and seasonal variations of 25 pharmaceutical residues in wastewater and drinking water treatment plants[END_REF][START_REF] Mompelat | Occurrence and fate of pharmaceutical products and by-products, from resource to drinking water[END_REF][START_REF] Togola | Multi-residue analysis of pharmaceutical compounds in aqueous samples[END_REF]. This generalized environmental contamination, outside the therapeutic context, leads to chronic human exposure to NSAIDs which physiological effects need to be documented. NSAIDs exert their pharmaceutical action by inhibiting the activity of cyclooxygenases COX-1 and COX-2 enzymes [START_REF] Brideau | A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors[END_REF][START_REF] Patrignani | Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs[END_REF][START_REF] Van Hecken | Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers[END_REF]. COX-1 and COX-2 are encoded by PTGS1 and PTGS2 (prostaglandinendoperoxide synthase) genes respectively and catalyze the bis-dioxygenation and reduction of Arachidonic Acid to Prostaglandin E2 (PGE2), mediator of neuropathic pain [START_REF] Ma | Does COX2-dependent PGE2 play a role in neuropathic pain?[END_REF][START_REF] Rouzer | Cyclooxygenases: structural and functional insights[END_REF]. For the CNS pain, NSAIDs are largely prescribed or indicated in case of headache or migraine in adult and their toxicity were reported in case of overdose [START_REF] Auriel | Nonsteroidal anti-inflammatory drugs exposure and the central nervous system[END_REF][START_REF] Becker | Acute Migraine Treatment in Adults[END_REF][START_REF] May | Hints on Diagnosing and Treating Headache[END_REF]. If adverse effects of NSAIDs are well identified in adult and if the communication exists to sensitize the consumers and to prevent CNS disorders, little is known about the effects of NSAIDs exposure during brain development. However, developmental exposure to NSAIDs exists as shown by several studies. First, placenta is not a barrier preventing NSAIDs fetal exposure since Siu (2000) demonstrated that after an administration of diclofenac to pregnant women before legal termination of pregnancy, this drug was measured in amniotic and coelomic fluids with a mean ratio of 0.95 for maternal plasma/fetal tissues. Fetal exposure was confirmed with the presence of ibuprofen, naproxen and indomethacin in the meconium of 101 infants in the Michigan [START_REF] Alano | Analysis of Nonsteroidal Antiinflammatory Drugs in Meconium and Its Relation to Persistent Pulmonary Hypertension of the Newborn[END_REF]. NSAIDs exposure is potentially prolonged to neonatal stage since ibuprofen and naproxen were measured in human breast milk at 0.37 µg/kg and 1.9 µg/kg respectively. In the same study, diclofenac was dosed at 0.09 µg/kg, ketoprofen at 0.15 µg/kg and naproxen at 0.35 µg/kg in powdered infant milk according the provenance [START_REF] Azzouz | Simultaneous Determination of 20 Pharmacologically Active Substances in Cow's Milk, Goat's Milk, and Human Breast Milk by Gas Chromatography-Mass Spectrometry[END_REF]. Knowing that NSAIDs inhibit the production of PGE2, we can ask ourselves if developmental exposure to NSAIDs has an impact on the brain differentiation. PGE2 is involved in the development of specific brain areas and in particular in hypothalamus and cerebellum differentiation. Its four receptors, EP1 to EP4 (or PTGER1-4: prostaglandin E receptor) are not ubiquitously distributed in the CNS. In rat, maximum expression of EP1 is found in pituitary gland and cerebellum, in hypothalamus and pituitary gland for EP2, in thalamus and hypothalamus for EP3 and cerebellum and cortex for EP4 [START_REF] Myren | Prostaglandin E2 receptor expression in the rat trigeminal-vascular system and other brain structures involved in pain[END_REF]. Several studies showed a direct implication of PGE2 in the development of the cerebellum and the preoptic area (POA), a subdivision of the hypothalamus controlling masculinization of adult sex behavior (Schwarz and McCarthy, 2008b). [START_REF] Amateau | A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2[END_REF] show, using POA neurons of newborn female rats (1-2 h), that PGE2 changes neuron morphology by increasing the number and density of dendritic spines. Using in vivo experiments, they reported the expression of PGE2 receptors EP1, EP2 and EP3 genes in the POA of PN0 female rat. In the same study, it was demonstrated that PGE2 is a mediator of E2 signal for the induction of the Spinophilin protein production, a marker of dendritic spines. Finally, [START_REF] Amateau | A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2[END_REF] have also identified the POA as a sexual dimorphic structure since they observed a greater Spinophilin protein quantity (two and half more) in newborn males than in newborn females [START_REF] Amateau | A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2[END_REF]. Two years later, the same team has demonstrated that PGE2 is directly implicated in the male sexualization of the developing POA and induced sex behavior in adult male rat. They also showed that E2 regulates the synthesis of PGE2 by upregulating PTGS2 expression and COX-2 enzyme production in the POA of 3 days old rat [START_REF] Amateau | Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior[END_REF]. The cerebellum is an area located in the rostral roof of the 4 th ventricle and functionally associated with emotional control, motor, cognitive, and social behaviors (Adamaszek et al., 2017;[START_REF] Voogd | The anatomy of the cerebellum[END_REF]. In 2012, Dean et al. brought the demonstration for the pivotal role of PGE2 in the development and functional acquisition of the cerebellum. In this study it was reported that PGE2 regulates the dendritic spines of Purkinje cells and cerebellum volume between PN7 and PN13 in male and female rats. This involvement of PGE2 in the differentiation of the cerebellum in this short window is directly associated with adult behavior induction like play, sensory threshold and object exploration [START_REF] Dean | Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period: Prostaglandins affect cerebellar development[END_REF]. These studies indisputably show a key role of PGE2 in the differentiation of POA and of the cerebellum and therefore of the brain at an early postnatal stage. NSAID-inhibition of PGE2 during brain development could have disruptive effects and could be a real concern. Very few studies were published on the toxicological effects of NSAIDs at environmental doses. Exposing common carps with NSAIDs-manufacturing plant effluent causes genotoxicity and apoptosis in blood cells [START_REF] Sanjuan-Reyes | NSAID-manufacturing plant effluent induces geno-and cytotoxicity in common carp ( Cyprinus carpio )[END_REF]. Other studies show, after environmental NSAIDS exposure, an induction of oxidative stress in fish, crustaceans and bivalves [START_REF] Gonzalez-Rey | Effects of non-steroidal anti-inflammatory drug (NSAID) diclofenac exposure in mussel Mytilus galloprovincialis[END_REF][START_REF] Novoa-Luna | Oxidative stress induced in Hyalella azteca by an effluent from a NSAID-manufacturing plant in Mexico[END_REF][START_REF] Sanjuan-Reyes | NSAID-manufacturing plant effluent induces geno-and cytotoxicity in common carp ( Cyprinus carpio )[END_REF]. Teratogenicity experiments using Xenopus embryos indicate that diclofenac at environmental doses causes malformation of several organs with acephaly, cephalic edema and a diminution of axial length [START_REF] Chae | Evaluation of developmental toxicity and teratogenicity of diclofenac using Xenopus embryos[END_REF]. No studies reporting NSAIDs effects on neurotoxicity in mammals are available, nevertheless inhibiting COX-1 and COX-2 enzymes and so preventing PGE2 production has a negative impact on brain development. In vitro incubation of POA neurons with indomethacin prevents dendritic spines formation and spinophilin production induced by PGE2 [START_REF] Amateau | A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2[END_REF]. Administration of indomethacin in newborn rats (6hrs of birth) blocks the production of spinophilin and decreases the density of dendritic spines in POA male rats (Amateau andMcCarthy, 2004, 2002). This structural modification of POA impacts the behaviors it controls. Indeed, exposure of neonate rats (between PN0 and PN1) to NSAID disturbs sexual behavior in adult males, not in adult females. Thereby a neonatal indomethacin treatment induces an decrease of sexual adult male behavior with an increasing of latency to mount, intromission, a decreasing of mounts and intromissions frequency and a cancellation of ejaculation [START_REF] Amateau | Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior[END_REF]. Nonneuronal cells of the POA are also sensitive to NSAIDs since POA microglial cells are more numerous and ameboid in male than female in neonate rats. This sexual dimorphism, dependent of PGE2, is abolished with indomethacin treatment inducing a loss of masculinization of the POA [START_REF] Lenz | Microglia are essential to masculinization of brain and behavior[END_REF]. Curiously the inhibition of COX-1 and COX-2 enzymes in the cerebellum has an opposite effect on neuron morphology but still impacts adult behavior. Treating neonate rats with NSAIDs (indomethacin and paracetamol) between PN7 and PN13 induces an increase of dendritic spine length of Purkinje cells only in male PN14 cerebellum and a modification of behaviors associated to this cerebral structure. Male adult rats exposed to NSAIDs in neonatal stage present a reduction of play behavior and the sensory threshold and an increase of object exploration time [START_REF] Dean | Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period: Prostaglandins affect cerebellar development[END_REF]. NSAIDs doses used in these studies are pharmaceutical and greatly extra-environmental, but a chronic NSAID developmental exposure with environmental doses and especially in the precocious postnatal window could have a real impact and remains largely underexplored.

When drugs become environmental pollutants: what about epigenetics consequences?

Recently, it became evident that epigenetics prior to or around the birth can profoundly modify brain development and can be linked to various neurodevelopmental syndromes (reviewed by [START_REF] Lo | Environmental Alterations of Epigenetics Prior to the Birth[END_REF]. Epigenetics disorders fit well with the time lag often observed for such syndromes, which may appear many years after exposure or in offspring. Although less is known about epigenetic consequences of in utero and perinatal chronic exposures to environmental pollutants, data presented in the current review ask questions about the putative role of epigenetics input, especially in behavioral changes observed between childhood and adulthood, or for the brain sexualization. For instance, in human, maternal exposure to environmental heavy metals during pregnancy is associated with differential DNA methylation in new-borns, especially on genes involved in neurogenesis [START_REF] Zeng | Differential DNA methylation in newborns with maternal exposure to heavy metals from an e-waste recycling area[END_REF]. This question is made relevant by the outcome of works establishing a causal link between a well-known endocrine disrupting compound, the Bisphenol A (BPA), and its epigenetic consequences. In mouse, BPA exposure modifies the expression of several genes involved in brain development by altering the genomic imprinting at various genetic loci. This effect is transmitted across generations. In addition, BPA has been suggested to affect the DNA methylation status, as well as histones post-translational modifications after in utero exposure (reviewed by [START_REF] Santoro | Neuro-toxic and Reproductive Effects of BPA[END_REF]. Similar effects are suspected about other pollutants, such as Permethrin [START_REF] Bordoni | Early impairment of epigenetic pattern in neurodegeneration: Additional mechanisms behind pyrethroid toxicity[END_REF], for which low dosage exposures during neonatal brain development led to significant reduction of H3K9me3 marks at Th and Nurr1 promoter regions, both genes being related to the dopamine-synthesis pathway. Although these pollutants are outside the scope of our review, they clearly illustrate the potential epigenetic impact of pollutants. What's about drugs when they are pollutants? Even if no studies are available at this level (epigenetics aftermath of drugs detected in the environment), data are now known on the epigenetic effect of drugs when administered during pregnancy or gestation, or around the perinatal period.

Antibiotics.

In addition to the overall effects of antibiotics on the nervous system (described above), various studies concerning the epigenetics alterations mediated by antibiotics have been published. It was demonstrated that zebrafishes are sensitive to a common biocide (Triclosan), when administrated to 8-cells developing larvae at low doses (50 or 100 µg/L), until hatching. This treatment modifies DNA methylation in a locusspecific manner (mainly within introns and intergenic sequences), while global DNA methylation is not affected. Consequently, the expression of few genes is modified. Interestingly, in zebrafish, antibiotics trigger mechanisms of acclimation leading to an increase resistance of organisms. Here, DNA methylations are likely to precede the adaptive response [START_REF] Falisse | DNA methylation and gene expression alterations in zebrafish early-life stages exposed to the antibacterial agent triclosan[END_REF]. Recently, a special attention was paid to how the composition of gut microbiota may contribute to establish epigenetic changes, leading to modulation of lifelong health and diseases, via the gut-brain axis. In humans, the role of maternal and neonatal nutrition, as well as microbiota composition has been reviewed by [START_REF] Indrio | Epigenetic Matters: The Link between Early Nutrition, Microbiome, and Long-term Health Development[END_REF]. The period during which epigenetic imprinting is the most active is referred as the 1,000 days period (from conception to the second anniversary). During this period the microbial colonization takes place first in utero, then after birth. Because the microbiota-related epigenetic regulation of gene expression could take place in various brain regions, the impact of the "quality" of the maternal microbiota has been suspected of importance in preventing or promoting brain development disorders [START_REF] Indrio | Epigenetic Matters: The Link between Early Nutrition, Microbiome, and Long-term Health Development[END_REF]. Evidence accumulate that a disturbed microbiota is related to various neurodegenerative diseases [START_REF] Quigley | Microbiota-Brain-Gut Axis and Neurodegenerative Diseases[END_REF]. In fact, gut microbiota is now looked as an important epigenetic regulator since some of their metabolites (as SCFAs) act as HDAC inhibitors, and play a role through DNA methylation, post-transcriptional histone modification, and chromatin restructuring, all together resulting in altering genes expression [START_REF] Kaur | Gut microbiome-mediated epigenetic regulation of brain disorder and application of machine learning for multiomics data analysis[END_REF]. By the way, pharmacological factors (such antibiotics) that modify microbiota can be related to the development of chronic diseases. In human, the predominant gut microbiota of pregnant women was associated to the postpartum methylation profile of their blood DNA and correlated with differential methylation status of gene promoters linked to cardiovascular diseases [START_REF] Kumar | Gut Microbiota as an Epigenetic Regulator: Pilot Study Based on Whole-Genome Methylation Analysis[END_REF]. Even if there is no direct evidence between epigenetics, antibiotics in the environment and neurodegenerative diseases, all the ingredients are there to consider a possible impact, including via pathways other than the microbiota.

Antidepressants.

Literature related to human risk constituted by antidepressants exposure at environmental doses during pre-and peri-natal development is poorly documented, but epigenetic consequences of maternal treatment during pre-and perinatal development are more documented (in animal models or in human clinical studies). Since fluoxetine is commonly prescribed for the treatment of depression in pregnancy, its impacts on in utero exposed children has been questioned, including at the epigenetics level. Alteration of DNA methylation levels has been detected in the hippocampus of rats that were exposed to fluoxetine during their development [START_REF] Silva | Maternal exposure to fluoxetine during gestation and lactation induces long lasting changes in the DNA methylation profile of offspring's brain and affects the social interaction of rat[END_REF]. This alteration correlates with modifications of the anxiety-related (social) behavior at adulthood, as result of an acquired imprinting. These studies converged with the findings of [START_REF] Boulle | Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring[END_REF], which demonstrate that fluoxetine modifies the epigenetic regulation of the hippocampal brain-derived neurotrophic factor (BDNF) coding gene, in the offspring of treated female. It was actually found that developmentally administered fluoxetine increases H3K27me3 levels at the BDNF promoter, in accordance with the decreased expression of BDNF mRNA in the hippocampus of offspring. More, these modifications were associated to increased depressive-related behaviors in adult female offspring, suggesting a long-term effect of fluoxetine treatment during gestation and/or lactation. Epigenetic effects of developmental exposure to fluoxetine were also suggested by studies on zebrafish [START_REF] Boulle | Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring[END_REF]. In addition, a 6-day exposure to fluoxetine at a fetus-relevant concentration inhibits cortisol secretion at adulthood in developmentally exposed zebrafish, and this alteration is persistent for three generations of unexposed progeny, as well as alterations in exploratory behaviors in males [START_REF] Vera-Chang | Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafish Danio rerio[END_REF]. Transcriptomic analysis of kidneys cells showed that fluoxetine exposure modified signaling pathways implicated in cortisol production on animals of the three generations. Neural effects are suspected to be involved through the HPA axis control [START_REF] Vera-Chang | Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafish Danio rerio[END_REF].

In human, the involvement of epigenetic mis-regulations is suggested through in vitro and in silico approaches using differentiated human neuroblastoma cells treated with a mixture of psychoactive pharmaceuticals including fluoxetine at environmentally relevant concentrations. A recent study identified alterations in neuronal gene sets expression associated with neurological disorders such as Autism Spectrum Disorders (ASD), Alzheimer's disease and schizophrenia. Among the genes exhibiting expression alterations, several genes coding synaptic proteins associated with ASD were affected [START_REF] Kaushik | Dysregulation of autismassociated synaptic proteins by psychoactive pharmaceuticals at environmental concentrations[END_REF].

Non-Steroid Anti-Inflammatory Drugs (NSAIDS).

Here again, no studies are available to prove a direct correlation between NSAIDS (as pollutants) and epigenetics alteration of brain development. But there is straight evidence of (i) epigenetic changes due to NSAIDS, (ii) the epigenetic control of brain feminization and (iii) the epigenetic control of PGE2 biosynthesis via an induced COX2 expression. In this context, it is tempting to propose that chronic exposure to NSAIDs may alter sexual behavior also through epigenetic mechanisms. Epigenetic changes due to NSAIDS have been studied in patients having various cancers. Clinical trials and ex-vivo analyses both suggest that aspirin and other NSAIDS induced changes in promoters' methylation, thus leading to gene silencing. This effect has been attributed to DNMT1 inhibition (reviewed by [START_REF] Yiannakopoulou | Targeting epigenetic mechanisms and microRNAs by aspirin and other non steroidal anti-inflammatory agents -implications for cancer treatment and chemoprevention[END_REF]. In animal studies, this local effect was found associated to an overall effect. Indeed, NSAIDS reverse global DNA hypomethylation in colon cancer rat-models. Finally, the fact that aspirin is known to acetylate proteins leads to assay whether it also acetylates histones, among other cellular proteins. This is actually the case, but it remains to establish whether this direct post-translational modification impairs gene expression [START_REF] Bhat | Aspirin acetylates multiple cellular proteins in HCT-116 colon cancer cells: Identification of novel targets[END_REF]. More recently, it has been found that Ibuprofen and Ibuprofen-CoA causes dose-dependent inhibition of histone acetylation, especially H2B K12/K15Ac and H3 K56Ac, in cultured cells [START_REF] Shrimp | Defining Metabolic and Nonmetabolic Regulation of Histone Acetylation by NSAID Chemotypes[END_REF]. Because epigenetics is involved in various endogenous and exogenous pathways to exert long-term control over gene expression, it was tempting to verify its role in estradiol-mediated brain masculinization, an effect herein described (see previous paragraph). Doing so, it was demonstrated that estradiol suppresses DNMT activity, leading to an overall DNA demethylation in male developing POA. This study confirms that feminization is an active repression of masculinization process, reinforced by epigenetics imprints [START_REF] Nugent | Brain feminization requires active repression of masculinization via DNA methylation[END_REF]. Finally, the epigenetic activation of the COX2 promoter by p300, a histone acetyl transferase, has been confirmed in activated monocytes, leading to PGE2 production [START_REF] Liu | Production of fever mediator PGE2 in human monocytes activated with MDP adjuvant is controlled by signaling from MAPK and p300 HAT: Key role of T cell derived factor[END_REF]. As mentioned before, increased COX2 expression and PGE2 production within dendritic spines leads to the hypothesis that COX2 is an active modulator of neuronal plasticity, involved in sex differentiation [START_REF] Amateau | A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2[END_REF]. The fact that COX2 activation appears finely and strictly controlled at the spatial level speaks up for an epigenetic control in neurons, as previously demonstrated in monocytes. In conclusion, albeit no direct evidence about epigenetic consequences of in utero and/or perinatal chronic exposures to drugs as environmental pollutants still exists, converging evidence suggests a possible impact. It therefore appears important not to overlook epigenetics effects when addressing this issue. Further studies remain to be done, especially in humans. The central issue being the dose at which these effects could be significant.

Non-invasive neuroimaging to advance knowledge on EDCs?

Evidence from epidemiological and experimental data of the close relationship between environmental contaminants and adverse functional and metabolic effects are mounting. Nevertheless, to date, there are very few dedicated non-invasive and translational methods with the ability to measure, demonstrate and validate a direct and specific link between the alteration of the function of the endocrine system and Endocrine disruptor compounds (EDCs) in-vivo in the brain. Methodologies and models are lacking for evaluating the mechanisms and pathways underlying the effects of EDCs and their development into diseases. Here, the potential of magnetic resonance (MR) techniques to assess risk factors induced by potential EDCs is introduced. In this paragraph, we aim to show in a non-exhaustive manner that noninvasive neuroimaging methods can be adapted to further advance and fasten knowledge on EDCs. (Haacke et al., 1999). That Nuclear Magnetic Resonance (NMR) techniques are powerful for the investigation of the structure, function and metabolism of the brain both in animal models and human is not to demonstrate anymore. MR imaging (MRI) is well known for its noninvasiveness, its important contrast between soft tissues and its high spatial resolution compared to other macro-imaging techniques (X rays, Positron Emission Tomography, Ultrasound). In addition, crucial technological developments have been carried out during the past 20 years and the advent of high magnetic field strength horizontal superconducting magnets (up to 11.7T in humans, up to 21T in rodents) coupled to improved hardware enabled an unprecedented increase of the sensitivity [START_REF] Hespel | Advances in High-Field MRI[END_REF][START_REF] Wald | Ultimate MRI[END_REF], the spatial and temporal resolutions and the development of novel molecular applications (Chemical Enhanced Saturation Transfer (CEST, PARACEST (De Leon-Rodriguez et al., 2009;[START_REF] Soesbe | Advantages of paramagnetic chemical exchange saturation transfer (CEST) complexes having slow to intermediate water exchange properties as responsive MRI agents: RESPONSIVE CHELATES FOR PARAMAGNETIC CEST IMAGING[END_REF], Hyperpolarisation techniques…). Despite all these assets, MR techniques lack sensitivity. Thus, molecular imaging possibilities are limited with extremely low compound concentrations (below millimolar). This poor sensitivity may explain the lack of interest for MR investigations on potential EDCs, which can be present in brain structures as traces only and which presence can rarely be measured and quantified with MRI or MR Spectroscopy (MRS) techniques. Interestingly, the MR literature represents an abundant source of knowledge on the potential effects of EDCs and their mechanisms since many studies investigated the dose-effect of various pharmaceuticals albeit not at the very low concentrations encountered in the environment.

Magnetic Resonance Imaging and Spectroscopy (MRI and MRS)

MR biomarkers could benefit knowledge on the endocrine effects of compounds.

MRI facilitates the in-vivo diagnosis, prognosis and therapeutic monitoring of various brain diseases such as cancer, neurodegenerative diseases and neuropsychiatric diseases (Alzheimer, Parkinson, dementia, epilepsy, multiple sclerosis…). Studies can be performed relatively fast, and longitudinally with little discomfort for patients. Therefore, assessment of repeatability and reproducibility of the outcome can be performed with increased accuracy. MR can also detect various conditions such as stroke and traumatic brain injury, hemorrhage, inflammation and edema. Endocrine disruption also involves metabolic alterations resulting in obesity, diabetes and liver diseases that remain to be understood... Multinuclear applications of MRS and chemical shift imaging (CSI) can be useful for investigating neurometabolic disorders. Moreover, metabolic changes can reveal the very early stages of disease prior to lesion detection [START_REF] Lei | Evolution of the Neurochemical Profile after Transient Focal Cerebral Ischemia in the Mouse Brain[END_REF]. This is important since EDCs' effects may develop over years and even decades or have consequences in adulthood only. Also, MR investigations demonstrated their usefulness upon assessment of the effects of various compounds [START_REF] Cherix | Metabolic signature in nucleus accumbens for anti-depressantlike effects of acetyl-L-carnitine[END_REF][START_REF] Kluza | Multi-parametric assessment of the anti-angiogenic effects of liposomal glucocorticoids[END_REF][START_REF] Padhani | Antivascular cancer treatments: functional assessments by dynamic contrast-enhanced magnetic resonance imaging[END_REF][START_REF] Wassmuth | Subclinical cardiotoxic effects of anthracyclines as assessed by magnetic resonance imaging-a pilot study[END_REF] both in humans and in animal models. The doseresponses of a variety of MR contrast agents such as gadolinium (Gd)-based contrast agents [START_REF] Prybylski | Impact of chelation timing on gadolinium deposition in rats after contrast administration[END_REF][START_REF] Robert | Contrast-to-Dose Relationship of Gadopiclenol, an MRI Macrocyclic Gadolinium-based Contrast Agent, Compared with Gadoterate, Gadobenate, and Gadobutrol in a Rat Brain Tumor Model[END_REF][START_REF] Woodard | Signal quality of single dose gadobenate dimeglumine pulmonary MRA examinations exceeds quality of MRA performed with double dose gadopentetate dimeglumine[END_REF] or iron oxide nanoparticles, were largely assessed [START_REF] Diana | Dose dependent side effect of superparamagnetic iron oxide nanoparticle labeling on cell motility in two fetal stem cell populations[END_REF][START_REF] Kim | Cerebral blood volume MRI with intravascular superparamagnetic iron oxide nanoparticles[END_REF]. Many other MR studies also investigated the effects of antidepressants [START_REF] Cherix | Metabolic signature in nucleus accumbens for anti-depressantlike effects of acetyl-L-carnitine[END_REF], antibiotics or analgesics [START_REF] Bar-Or | Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study[END_REF][START_REF] Jantzie | Prenatal opioid exposure: The next neonatal neuroinflammatory disease[END_REF]. MR techniques (Diffusion, Perfusion, blood oxygen level-dependent (BOLD) functional MRI…) can be used to assess the dose-impact of these compounds using surrogate markers of various parameters (permeability, vessel radius, water diffusion, blood volume, blood flow…) that can be mapped on a voxel-by-voxel basis thereby also displaying the heterogeneity and extent of the effects. Moreover, the impact of a defined compound on the behavior or alterations of this behavior can also be investigated with functional MR techniques.

Investigating the effects of antidepressants and NSAIDs with MR techniques.

With advanced technological developments in MRI across the past 20 years, BOLD-fMRI and resting-state-(RS)-fMRI became the methodologies of choice for investigating neuropsychiatric disorders. Task-based fMRI has identified altered functional activity in a wide spectrum of psychiatric disorders while RS-fMRI is recognized as a predictor of treatment response in major depressive disorder (MDD), schizophrenia, anxiety disorders and autism where brain connectivity is often altered. fMRI was also extensively used for a better understanding of pain and analgesiarelated phenomena [START_REF] Borsook | Breaking down the barriers: fMRI applications in pain, analgesia and analgesics[END_REF]. There has recently been increased use of RS-fMRI in the context of studies addressing brain network dynamics involved in response to antidepressant and analgesics treatments, both in terms of predicting response to treatment as well as understanding changes in functional brain connectivity after effective treatments. Dichter et al. (2014) reviewed the linkages between RS-fMRI and treatment response in MDD thereby identifying specific biomarkers and specific patterns of brain network dynamics affected by antidepressants. A variety of antidepressant substances that have been increasingly examined with these MR techniques demonstrated to have toxic effects on the reproductive system and hormones [START_REF] Dichter | A systematic review of relations between resting-state functional-MRI and treatment response in major depressive disorder[END_REF]. This is the case of ketamine, which recently attracted a large interest for its impact on metabolism [START_REF] Bednarik | Effect of Ketamine on Human Neurochemistry in Posterior Cingulate Cortex: A Pilot Magnetic Resonance Spectroscopy Study at 3 Tesla[END_REF][START_REF] Qi | Toxic effects of ketamine on reproductive system via disrupting hypothalamic-pituitarytesticular axis[END_REF]. Fluoxetine and norfluoxetine were also abundantly studied with MRI and MRS and are well-known EDCs present in aquatic systems [START_REF] Mennigen | Pharmaceuticals as Neuroendocrine Disruptors: Lessons Learned from Fish on Prozac[END_REF]. Moreover, several agents used to correct the endocrine imbalance were also employed as antidepressants such as melatonin and glucocorticoids [START_REF] Antonioli | Neuroimmune endocrine effects of antidepressants[END_REF]. Numerous effects of these agents was examined and identified [START_REF] Kalafatakis | Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man[END_REF]. In particular, glucocorticoid receptors are recognized as important targets for EDCs. Of note, important knowledge on the underlying effects of these agents and their potential markers examined with MR techniques was accumulated. An important database exists therefore allowing the identification of risk factors linked to EDCs. In addition, important cohorts of responder and non-responder patients followed over years could serve to examine the long-term effects of a variety of compounds and their mixture. Their physiological and endocrine status is already often followed across years.

Neuroimaging techniques have also a considerable role to play in the more appropriate development of analgesics. Most of them only have a significant effect on a minority of patients. Despite the promise of interesting signs of progress, the use of mild analgesics such as paracetamol, ibuprofen and aspirin in the general public and pregnant women increases and is generally perceived to be safe [START_REF] Thiele | Acetaminophen and pregnancy: short-and long-term consequences for mother and child[END_REF]. Unfortunately, they also have potent disrupting effects on hormonal homeostasis, leading to congenital malformation in both animals and humans through antiandrogenic mechanisms [START_REF] Kristensen | Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism[END_REF][START_REF] Kristensen | Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat[END_REF]. Neuroimaging techniques are usually effective at discriminating responsive and non-responsive patients and reveal novel targets, which could be of value for a better understanding of the endocrine mode of action of these compounds.

Metabolism and EDCs.

EDCs interfere with the endocrine system by altering mechanisms linked to hormone secretion or elimination. EDCs can also mimic hormone action. All these modes of action can disrupt the regulation of general homeostasis of the body and contribute to adverse metabolic phenotypes. EDCs can also predispose patients to several metabolic syndromes and alter nutrient ingestion and metabolism. Moreover, specific individuals may be more affected than others such as the developing fetus, which is more sensitive to endocrine perturbations. Fetus exposure to EDCs may cause irreversible effects that may become detectable later in life. In this context, MRS can be useful. An example was given by [START_REF] Kunz | Developmental and metabolic brain alterations in rats exposed to bisphenol A during gestation and lactation[END_REF] who used proton MRS at 9.4T to assess the effect of perinatal exposure to bisphenol A (BPA) on cerebral structural development and metabolism after birth in rat pups. On postnatal day 20, in vivo metabolite concentrations in the rat pup hippocampus were measured. Exposure to low dose BPA during gestation and lactation resulted in subtle and regional neuronal and glial alterations in brain development in offspring. Furthermore, BPA exposure led to significant changes in the Glutamate to Aspartate ratio in the hippocampus, which is postulated to reflect impaired mitochondrial function and probably implicates a reduced ability of the brain to oxidize glucose especially in conditions of elevated energetic demand [START_REF] Kunz | Developmental and metabolic brain alterations in rats exposed to bisphenol A during gestation and lactation[END_REF]. The changes observed after prenatal BPA exposure will likely imply long-lasting effects on cognitive development and function. While such studies are needed and somehow not difficult to realize, investigations of EDCs effects in huge cohorts of humans may benefit the assessment of the levels of exposure to EDCs. Such screening studies can be performed with NMR metabolomics and were proposed by the EDCMET project [START_REF] Küblbeck | The EDCMET Project: Metabolic Effects of Endocrine Disruptors[END_REF]. Using serum NMR platforms, NMR spectroscopy can simultaneously quantify 230 metabolic features such as serum proteins, lipids, fatty acids, glycolysis substrates, amino acids, ketone bodies and many other molecules to obtain signature metabolic profiles affected by EDCs. Although few MR studies have been conducted yet in the context of pharmaceutical EDCs, the specific case of MR contrast agents can illustrate the potential of MRI and MRS for the detection and evaluation of endocrine disruption. Gd is a heavy metal of the lanthanide group. Chelated forms of Gd are used in MRI and MR angiography to avoid the toxicity of Gd 3+ . Recently, tissue deposition of Gd was demonstrated in various rodent and human tissues of the body [START_REF] Sato | Tissue gadolinium deposition in renally impaired rats exposed to different gadolinium-based MRI contrast agents: evaluation with inductively coupled plasma mass spectrometry (ICP-MS)[END_REF][START_REF] Wáng | Total gadolinium tissue deposition and skin structural findings following the administration of structurally different gadolinium chelates in healthy and ovariectomized female rats[END_REF] and of the brain [START_REF] Gulani | Gadolinium deposition in the brain: summary of evidence and recommendations[END_REF]. Free Gd 3+ ions induced cell death, oxidative stress and accumulation of reactive oxygen species (ROS) in rat cortical neurons [START_REF] Feng | Gadolinium triggers unfolded protein responses (UPRs) in primary cultured rat cortical astrocytes via promotion of an influx of extracellular Ca2+[END_REF]). Briner et al. (2000) reported important behavioral responses of mice exposed to lanthanides with consequences on their development further confirmed by Feng et al. (2006) who also showed altered DNA and protein/DNA concentrations in the brain. Interestingly, the current literature does not report longitudinal BOLD-fMRI or perfusion studies in animal models or humans combined with behavioral assessments following Gd injections although 30 million doses are consumed each year [START_REF] Guo | Gadolinium Deposition in Brain: Current Scientific Evidence and Future Perspectives[END_REF]. Non-invasive functional evaluations could be insightful as predictive factors of parkinsonism since Gd deposition in the dentate nucleus and the globus pallidus induced symptoms [START_REF] Welk | Association Between Gadolinium Contrast Exposure and the Risk of Parkinsonism[END_REF] but require longterm follow up. In the context of EDCs, cell cultures demonstrated that toxic effects on thyroid hormones depended on the chemical structure and dose of Gd-based contrast agents [START_REF] Ariyani | Effects of Gadolinium-Based Contrast Agents on Thyroid Hormone Receptor Action and Thyroid Hormone-Induced Cerebellar Purkinje Cell Morphogenesis[END_REF] but no in-vivo study has been conducted to date. Again, as described earlier for other pharmaceuticals, Gd-based contrast agents are difficult to remove with the usual sewage treatment technology. Amounts of Gd-based contrast agents in wastewater significantly increased with the increasing use of MRI technology [START_REF] Brünjes | Anthropogenic gadolinium in freshwater and drinking water systems[END_REF][START_REF] Inoue | Impact on gadolinium anomaly in river waters in Tokyo related to the increased number of MRI devices in use[END_REF] emphasizing the need to change medical practices. More recently, manganese ions (Mn 2+ ) attracted overwhelming interest owing to their paramagnetic properties enabling them to be used as contrast agents and to depict the rodent brain cytoarchitecture with unprecedented dose-dependent MR contrast. A better understanding of their toxicity was also obtained using MRS (Just et al., 2011;Just and Gruetter, 2011). Mn-induced neurotoxicity is well known with reference to occupational Mn exposure. Due to the risk exposure of smelters and welders, it was shown that Mn-exposure disrupted the endocrine systems of Mn-exposed workers [START_REF] Long | Vulnerability of welders to manganese exposure--a neuroimaging study[END_REF]. Mn uptake was reported in various human brain structures (caudate nucleus, substantia nigra, pituitary gland, ventromedial hypothalamus…). A wealth of human studies demonstrated that significant hyperintensities in T1-weighted MR images of Mn-exposed workers occur [START_REF] Criswell | MRI Signal Intensity and Parkinsonism in Manganese-Exposed Workers[END_REF]. Various MR methodologies can be used to identify Mn toxicity: the pallidal index (PI) can be used to quantify hyperintensities due to increased Mn 2+ concentrations but relaxometry may also quantify Mn content while proton MRS can be useful in detecting the impact of Mn on metabolites (Just et al., 2011). Notably, metabolites can be markers of Mn-induced Parkinson or encephalopathic symptoms [START_REF] Peres | Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies[END_REF]. Many other metal compounds play a role as EDCs (reviewed in [START_REF] Iavicoli | The effects of metals as endocrine disruptors[END_REF]). MRI/MRS can identify the influence of these metals on the endocrine system by exploring their mechanisms of action, their content or their effects on behavior. Iavicoli et al ( 2009) also pointed at the lack of studies on the effects of mixtures of these metals. Some of them such as Zinc (Zn) or Europium (Eu) or copper (Cu), iron (Fe3+) can also be used in the chemical structure of contrast agents .In an identical manner to Gdbased compounds, metal compounds used in the medical practice find their way to rivers, where they may have deleterious effects on invertebrates and vertebrates [START_REF] Iavicoli | The effects of metals as endocrine disruptors[END_REF]. In conclusion, the in-vivo detection of EDCs' amounts and an improved understanding of their mechanisms and modes of action are much needed to validate the associated risks factors and determine appropriate predictive markers. But this is challenging. Magnetic Resonance techniques can represent a major tool in this context with longterm accumulated data and already developed methodologies that just need to be used.

Discussion

Are pharmaceutical drugs endocrine disruptor compounds?

The pharmaceutical drugs considered in this article (antibiotics, antidepressants, antiinflammatories) induce neural effects. Whether all these neural effects occur through an endocrine disrupting mode of action still needs to be thoroughly documented, in particular at doses close to the environmental exposure. There are, however, several evidences highlighted in this article that suggest that these substances may act as endocrine disruptors. For antibiotics, the evidences in favor of an endocrine disrupting mode of action are provided by the studies performed in aquatic models and using low environmentally relevant doses of these substances. In fish, exposure to these molecules impaired reproduction probably through modifications of the gonadotropic axis and steroidogenesis [START_REF] Kim | Effects of chronic exposure to cefadroxil and cefradine on Daphnia magna and Oryzias latipes[END_REF][START_REF] Kim | Effect of chronic exposure to acetaminophen and lincomycin on Japanese medaka (Oryzias latipes) and freshwater cladocerans Daphnia magna and Moina macrocopa, and potential mechanisms of endocrine disruption[END_REF]. The thyroid axis was also targeted leading to affected growth and development [START_REF] Yu | Low-dose effects on thyroid disruption in zebrafish by long-term exposure to oxytetracycline[END_REF]. In mammals, such studies are still lacking. In particular, whether the effects induced by exposure to antibiotics on social and mood behaviors in children [START_REF] Slykerman | Antibiotics in the first year of life and subsequent neurocognitive outcomes[END_REF] and animal models [START_REF] Degroote | Maternal gut and fetal brain connection: Increased anxiety and reduced social interactions in Wistar rat offspring following peri-conceptional antibiotic exposure[END_REF][START_REF] Leclercq | Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior[END_REF][START_REF] Tochitani | Administration of Non-Absorbable Antibiotics to Pregnant Mice to Perturb the Maternal Gut Microbiota Is Associated with Alterations in Offspring Behavior[END_REF] involve a disruption of neuroendocrine systems needs further investigation. It is, however, important to keep in mind that these behaviors are known to be regulated by sexual and thyroid hormones. The SSRIs antidepressants such as fluoxetine or sertraline, the most commonly prescribed ones, showed to affect social, anxiety-related and reproductive behaviors in aquatic species after developmental exposure to doses compatible with environmental contamination [START_REF] Sehonova | Effects of waterborne antidepressants on non-target animals living in the aquatic environment: A review[END_REF]. Such alterations suggest endocrine disruption effects triggering the hypothalamic-pituitary-adrenal and gonadotropic axis [START_REF] Mennigen | Pharmaceuticals as Neuroendocrine Disruptors: Lessons Learned from Fish on Prozac[END_REF]. For human assessment of the risk associated with developmental antidepressant exposure, the literature deals with developmental exposure to SSRIs at pharmacological doses, in the context of maternal treatment for major depressive disorder during pregnancy and/or postpartum depression. Studies in rodents report long-lasting endocrine and behavioral alterations on the developmentally exposed offspring, and neural alterations are described, susceptible to be responsible for these long-term effects. In the study of Soiza-Reilly et al. (2019), it was shown that all the inhibitors tested exerted endocrine disrupting effects, with different mechanisms from one molecule to another. Therefore, potential effects of SSRIs as endocrine disruptors at environmental doses have to be investigated on mammal models. The NSAIDs interfere with the E2 dependant mechanisms during brain development. One of the numerous actions of E2 signal is to activate COX-1 and COX-2 enzymes for the conversion of Arachidonic Acid to PGE2 [START_REF] Hermenegildo | Cyclooxygenases Regulation by Estradiol on Endothelium[END_REF]. PGE2 have a key role in the brain sexualization by regulating the male differentiation of the preoptic area and cerebellum (Amateau andMcCarthy, 2004, 2002). So, the inhibition by NSAIDs of COX enzymes and consequently of PGE2 production during CNS development results in a reduction of sexual behaviour, play behavior, and of the sensory threshold as well as an increase of object exploration time in adult male [START_REF] Amateau | Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior[END_REF][START_REF] Dean | Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period: Prostaglandins affect cerebellar development[END_REF]. At the cellular level, NSAIDs impact the morphology of neuronal and microglial cells by inhibiting spinophilin production, a protein specific to dendritic spines (Amateau andMcCarthy, 2004, 2002;[START_REF] Lenz | Microglia are essential to masculinization of brain and behavior[END_REF]. Since microglia produce prostaglandins, express prostaglandin receptors, and are activated during the critical period for sexual differentiation, some authors have hypothesized a role of microglia in E2-induced PGE2 production in the POA [START_REF] Welberg | Microglia maketh the male[END_REF]. Microglial PGE2 has been shown to play an important role in the proliferation of astrocytes, identifying PGE2 as a key neuro-inflammatory molecule that triggers the pathological response related to the uncontrollable proliferation of astrocytes [START_REF] Zhang | Prostaglandin E2 released from activated microglia enhances astrocyte proliferation in vitro[END_REF]. These results are important to elucidate the role of activated microglia and PGE2 in astrocyte proliferation and to suggest a potential disturbance in chronic exposure to anti-inflammatory agent molecules. Even if reported studies in this review have used pharmacological doses, whether antibiotics, antidepressants and anti-inflammatories induce adverse effects on the central nervous system development at environmental exposure remains to be answered.

Pharmaceutical drug exposure and susceptibility to neurodegenerative disease, what about epigenetic?

The epigenome is responsible for the functional use and stability of information within the genome, but in contrast to the stable genetic material, the epigenome fluctuates in response to environmental exposures. Pharmaco-epigenetics is an emerging aspect of the usual pharmaco-vigilance. It concerns alterations in gene expression of drugmetabolizing enzymes and transporters that result in interindividual variations in drug responses. During the developmental period from newborn to childhood, interindividual variations are combined with changes related to the differentiation and growth of tissues and organs. All are under epigenetic control, and therefore sensitive to epigenetic deregulations. As previously mentioned, about nothing is known about relationships between epigenetic and pharmaceutical pollutants (i.e. low-doses and long exposures). However, there is growing evidence suggesting such relationships.

(1) Brain development and neuro-degenerative diseases are under epigenetic control. Indeed, individuals with neuropsychiatric and neuro-degenerative diseases display epigenetic brain programming disturbances (Abdolmaleky et al., 2008). Studies of monozygotic twins discordant for schizophrenia and bipolar disorders reveal a significant difference in DNA hypomethylation of gene networks and pathways directly relevant to psychiatric disorders and neurodevelopment. Analyses of post-mortem brain tissues reveal DNA hypomethylation in psychosis patients (when compared to controls), for the same DNA regions than those identified in twins [START_REF] Dempster | Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder[END_REF]. Brain masculinization is a consequence of testosterone production which epigenetically regulates sex differences in the neuronal structure of some hypothalamus nuclei [START_REF] Mccarthy | The Epigenetics of Sex Differences in the Brain[END_REF]. (2) Pharmaceutical drug exposure alters epigenetic pathways of brain development. Indeed, in utero exposure to many substances results in neuronal injury related to epigenetic changes and results in longterm neuro-developmental impairment in the offspring. More, transgenerational epigenetics may also explain the fact that developmental abnormalities, impairment in learning and memory, and attention deficit can occur even in the absence of direct fetal exposure, when drugs are used prior to conception [START_REF] Neri | Drugs of Abuse in Pregnancy, Poor Neonatal Development, and Future Neurodegeneration. Is Oxidative Stress the Culprit?[END_REF]. (3) The consequences of intrauterine exposure to drugs can appear very late, at adolescence or adulthood. As an example, prenatal exposure to xenobiotics probably leads to alteration of the hypothalamic-pituitary-adrenal (HPA) axis. These alterations are believed to increase the susceptibility to adult neuropsychiatric disorders (such as depression and schizophrenia). Among the possible mechanisms of action, xenobiotics can directly induce epigenetic alterations, modifying the expression of main fetal genes (such as hippocampal glucocorticoid receptor, adrenal steroidogenic acute regulatory protein…) [START_REF] Zhang | Prenatal xenobiotic exposure and intrauterine hypothalamus-pituitary-adrenal axis programming alteration[END_REF]. To conclude, it appears essential to keep in mind that epigenetic deregulations are a powerful way to account for time-lagged and even transgenerational effects, often observed in neurodegenerative pathologies and could be crucial to validate the involvement of environmental pollutants at their onset (during childhood or later in life).

Alternative methods for the assessment of the impact of endocrine disruptor compounds on the central nervous system: A large set of MR-based data and know-how has been accumulated across years to evaluate brain dose-responses to various pharmaceuticals. This knowledge could be advantageous to evaluate in-vivo the impact of various molecules acting as EDCs. Long-term follow-up of changes in behaviour, neuroanatomy, function and metabolism of EDC-exposed populations could be envisaged and associated with various measurements in drinking water or sewage. Moreover, important databases of the effects of antidepressants, antibiotics and NSAIDS on brain function and metabolism exist and could be helpful for modelling purposes. Although novel methods exist, one important disadvantage of MR techniques is their low sensitivity, which does not permit the detection of traces or very low doses of pharmaceuticals, impeding reliable and direct attribution of longitudinal changes to specific molecules considered as EDCs. Nevertheless, MR can be efficiently coupled to other imaging modalities such as ultrasound, CT or PET, which have molecular imaging possibilities. Nowadays, PET-MRI is a well-accepted technique both in rodents and humans allowing the coupling of the molecular potential of PET to the high spatial resolution of MRI [START_REF] Musafargani | PET/MRI: a frontier in era of complementary hybrid imaging[END_REF] with little-invasiveness and could be effective at EDC detection at very low doses. While in vivo analysis is of paramount importance, the use of MR microscopy and MR spectroscopy to evaluate ex-vivo and in-vitro specimens is not to be neglected. In this regard, one can think of the systematic and longitudinal analysis of water samples with high-resolution MR techniques (HR MAS) [START_REF] Lucas-Torres | Current Developments in µMAS NMR Analysis for Metabolomics[END_REF], which could reveal the presence of various substances and can be coupled to mass-spectroscopy techniques [START_REF] Emwas | The Strengths and Weaknesses of NMR Spectroscopy and Mass Spectrometry with Particular Focus on Metabolomics Research[END_REF].

Conclusion

Scientific literature reported in this review shows real adverse effects of pharmaceutical products present in the environment on the development of the central nervous system. The risk for future generations could be a concern and has to be evaluated. Indeed, food and water for human consumption are contaminated and the exposure to these pharmaceutical substances occurs during the adult life but also at earlier stages including foetal development. The chronic exposure to these drugs even at environmental doses for human but also farm animals and wild life is, at this time, largely underestimated. Metrology studies have to be multiplied to measure these pharmaceuticals in the whole environment (macro and microenvironment) to define our exposome and evaluate the risk of this environmental exposure. The question of the implication of the microbiota is emerging, futures studies have to precise if these drugs exert their adverse effects on the CNS development by disrupting the gut-brain axis.

Bibliography

Abdolmaleky, H.M., Zhou, J.-R., Thiagalingam, S., Smith, C.L., 2008. Epigenetic and pharmacoepigenomic studies of major psychoses and potentials for therapeutics. Pharmacogenomics 9, 1809-1823. https://doi.org/10.2217/14622416.9.12.1809 Adamaszek, M., D'Agata, F., Ferrucci, R., Habas, C., Keulen, S., Kirkby, K.C.,

Graphical Abstract Caption

Ingested pharmaceutical drugs have therapeutic effects on the brain that have been widely characterized with invasive and non-invasive techniques. A number of these molecules have known endocrine effects. Among the most used therapeutic compounds, antidepressants, antibiotics and NSAIDs account for a large percentage. They are excreted via urine and feces and can be found at environmental doses in the sewage and the wastewater, where they affect acquatic milieux and can be reabsorbed by humans. They become potential endocrine disruptor compounds. What are their neural effects and mechanisms ? How can they be measured ? Can neuroimaging techniques contribute to the efforts for a better assessment of endocrine risk factors with their accumulated knowledge and non-invasive markers (Connectivity studies, fMRI, MR Spectroscopy…)? The present review addresses the current status and needs of research on pharmaceutical pollutants with endocrine-disrupting modes of action.