Design and Synthesis of Novel N-Benzylidene Derivatives of 3-Amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine under Microwave, In Silico ADME Predictions, In Vitro Antitumoral Activities and In Vivo Toxicity.

The synthesis of a series of new N-benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine 10(a-l) bearing two points of molecular diversity is reported. These new compounds were synthesized in five steps including two steps under microwave dielectric heating. They were fully characterized using 1H and 13C NMR, FTIR and HRMS. The in silico physicochemical properties of compounds 10(a-l) were determined according to Lipinski's rules of five (RO5) associated with the prediction of their bioavailability. These new compounds 10(a-l) were tested for their antiproliferative activities in fibroblasts and eight representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3, MCF7 and PANC1). Among them, the compounds 10h and 10i showed sub-micromolar cytotoxic activity on tumor cell lines (0.23 < IC50 < 0.3 µM) and no toxicity on fibroblasts (IC50 > 25 µM). A dose-dependent inhibition of Store-Operated Ca+2 Entry (SOCE) was observed in the HEK293 cell line with 10h. In vitro embryotoxicity and angiogenesis on the mCherry transgenic zebrafish line showed that 10h presented no toxic effect and no angiogenic effect on embryos with a dose of 5 µM at 72 hpf.

Maternal probiotic Lactocaseibacillus rhamnosus HN001 treatment alters postpartum anxiety, cortical monoamines, and the gut microbiome.

Peripartum mood and anxiety disorders (PMADs) affect 15-20% of peripartum women and are well known to disrupt infant caregiving. A recent study in humans reported that anxiety and depressive symptoms were alleviated by peripartum treatment with the probiotic, Lactocaseibacillus rhamnosus HN001. The current study determined the effects of chronic Lactocaseibacillus rhamnosus HN001 (HN001) treatment on postpartum affective and caregiving behaviors in a laboratory rodent model. Female rats were given probiotic overnight in their drinking water, or untreated water, from the first day of pregnancy through postpartum day 10. To determine whether the HN001 effects were influenced by a background of stress, half the females underwent chronic variable pregnancy stress and the other half remained undisturbed. The results revealed that, even without pregnancy stress, HN001 reduced postpartum anxiety-related behavior, increased variability in behavioral fragmentation when dams interacted with pups, increased time away from pups, and decreased prefrontal cortex norepinephrine (NE), dopamine (DA) and serotonin (5-HT). Probiotic plus stress consistently reduced the latency to float in the forced swim test, increased DA and 5-HT turnovers in the prefrontal cortex, increased hippocampal NE, and reduced hypothalamic DA. Fecal microbe alpha and beta diversities were lower postpartum than prepartum, which was prevented by the probiotic treatment and/or stress. Across the entire sample lower postpartum anxiety behavior was associated with lower fecal Bacteroides dorei. This study reveals novel information about how L. rhamnosus HN001 influences postpartum behavior and microbiota-gut-brain physiology in female laboratory rats, with implications for probiotic supplement use by pregnant and postpartum women.

Gestational stress and perinatal SSRIs differentially impact the maternal and neonatal microbiome-gut-brain axis.

Selective serotonin reuptake inhibitors (SSRIs) are the most popular antidepressant medications used to manage perinatal mood disturbances, yet our understanding of how they affect the microbiome-gut-brain axis of the mother and offspring is limited. The purpose of this study was to determine how peripartum SSRI treatment may prevent the effects of gestational stress on plasticity in the maternal hippocampus, plasticity in the neonatal brain and related changes in gut microbiota. To do this Sprague-Dawley female rats were left untreated or subjected to unpredictable stress during pregnancy. Half of the females were supplemented daily with fluoxetine. On postpartum day 2 brains were collected for measurement of plasticity (neurogenesis and microglia content) in the maternal hippocampus and in the neonatal brain. Glucocorticoid receptor density was also investigated in the maternal hippocampus. Microbiota composition was analyzed in fecal samples of dams during and after pregnancy, and colon tissue samples from offspring on postnatal day 2. Main findings show there are significant changes to the maternal microbiome-gut-brain axis that may be fundamental to mediating plasticity in the maternal hippocampus. In addition, there is significant impact of gestational stress on neonatal gut microbiota and brain microglia density, while the effects of SSRIs are limited. This is the first study to explore the impact of gestational stress and SSRIs on the microbiome-gut-brain axis in the mother and neonate. Findings from this study will help inform pathways to intervention strategies including stress reduction techniques and/or microbiota targeted nutritional approaches directed towards improving maternal gut health and outcomes for mother and neonate.

Revealing the Increased Stress Response Behavior through Transcriptomic Analysis of Adult Zebrafish Brain after Chronic Low to Moderate Dose Rates of Ionizing Radiation.

High levels of ionizing radiation (IR) are known to induce neurogenesis defects with harmful consequences on brain morphogenesis and cognitive functions, but the effects of chronic low to moderate dose rates of IR remain largely unknown. In this study, we aim at defining the main molecular pathways impacted by IR and how these effects can translate to higher organizational levels such as behavior. Adult zebrafish were exposed to gamma radiation for 36 days at 0.05 mGy/h, 0.5 mGy/h and 5 mGy/h. RNA sequencing was performed on the telencephalon and completed by RNA in situ hybridization that confirmed the upregulation of oxytocin and cone rod homeobox in the parvocellular preoptic nucleus. A dose rate-dependent increase in differentially expressed genes (DEG) was observed with 27 DEG at 0.05 mGy/h, 200 DEG at 0.5 mGy/h and 530 DEG at 5 mGy/h. Genes involved in neurotransmission, neurohormones and hypothalamic-pituitary-interrenal axis functions were specifically affected, strongly suggesting their involvement in the stress response behavior observed after exposure to dose rates superior or equal to 0.5 mGy/h. At the individual scale, hypolocomotion, increased freezing and social stress were detected. Together, these data highlight the intricate interaction between neurohormones (and particularly oxytocin), neurotransmission and neurogenesis in response to chronic exposure to IR and the establishment of anxiety-like behavior.

Olfactory detection of trace amounts of plant volatiles is correlated with testosterone in a passerine bird.

In response to damage by insects, plants release herbivore-induced plant volatiles (HIPVs) into the air. Insectivorous birds exploit these cues and, consequently, reduce the damages inflicted to the plants. However, little is known about whether they solely use HIPVs as foraging cues, or if they also use them to modulate traits linked to reproduction. As caterpillars are the primary food source required for insectivorous birds to raise offspring, their ability to locate and predict future peaks in caterpillar biomass using olfaction is likely to be advantageous. Therefore, we tested whether an insectivorous songbird that naturally inhabits oak dominated forests can be trained to detect early spring infestation by hatchling caterpillars, at a time when oaks begin bursting, and birds prepare to breed. Tree buds were either infested with caterpillars or left as a control and visually obscured in a Y-Maze choice test. Additionally, we measured testosterone and 17ß-estradiol as they influence olfactory perception in mammals and are linked to reproduction in vertebrates. After being trained to associate the presence of HIPVs with that of food, blue tits spent more time with, were more active around, and more frequently chose to first visit the infested trees, showing that blue tits can smell caterpillar activity. Males with higher testosterone spent more time around infested trees, suggesting that foraging behavior during the pre-breeding season is linked with a major reproductive signal. There was no relationship between foraging and estradiol in females. These results are an important foundation for further investigation of the role of hormones in avian olfaction and how smell may be useful for making breeding decisions that could improve reproductive success.

Fos expression in the medial preoptic area and nucleus accumbens of female Japanese quail (Coturnix japonica) after maternal induction and interaction with chicks.

The neural system underlying maternal caregiving has often been studied using laboratory rodents and a few other mammalian species. This research shows that the medial preoptic area (mPOA) integrates sensory cues from the young that, along with hormonal and other environmental signals, control maternal acceptance of neonates. The mPOA then activates the mesolimbic system to drive maternal motivation and caregiving activities. How components of this neural system respond to maternal experience and exposure to young in non-mammals has rarely been examined. To gain more insight into this question, virgin female Japanese quail (Coturnix japonica) were induced to be maternal through four days of continuous exposure to chicks (Maternal), or were not exposed to chicks (Non-Maternal). Chicks were removed overnight from the Maternal group and half the females from each group were then exposed to chicks for 90 minutes (Exposed), or not exposed to chicks (Non-Exposed), before euthanasia. The number of Fos-immunoreactive (Fos-ir) cells was examined as a marker of neuronal activation. As expected, repeated exposure to chicks induced caregiving behavior in the Maternal females, which persisted after the overnight separation, suggesting the formation of a maternal memory. In contrast, Non-Maternal females were aggressive and rejected the chicks when exposed to them. Exposed females, whether or not they were given prior experience with chicks (i.e., regardless if they accepted or rejected chicks during the exposure before euthanasia), had more Fos-ir cells in the mPOA compared to Non-Exposed females. In the nucleus accumbens (NAC), the number of Fos-ir cells was high in all Maternal females whether or not they were Exposed to chicks again before euthanasia. In the lateral bed nucleus of the stria terminalis, a site involved in general stress responding, groups did not differ in the number of Fos-ir cells. These data indicate a conserved role for the mPOA and NAC in maternal caregiving across vertebrates, with the mPOA acutely responding to the salience rather than valence of offspring cues, and the NAC showing longer-term changes in activity after a positive maternal experience even without a recent exposure to young.

Impacts of bisphenol A analogues on zebrafish post-embryonic brain.

Bisphenol A (BPA) is a widely studied and well-recognised endocrine-disrupting chemical, and one of the current issues is its safe replacement by various analogues. Using larva zebrafish as a model, the present study reveals that moderate and chronic exposure to BPA analogues such as bisphenol S, bisphenol F and bisphenol AF may also affect vertebrate neurodevelopment and locomotor activity. Several parameters of embryo-larval development were investigated, such as mortality, hatching, number of mitotically active cell, as defined by 5-bromo-2'-deoxyuridine incorporation and proliferative cell nuclear antigen labelling, aromatase B protein expression in radial glial cell and locomotor activity. Our results show that exposure to several bisphenol analogues induced an acceleration of embryo hatching rate. At the level of the developing brain, a strong up-regulation of the oestrogen-sensitive Aromatase B was also detected in the hypothalamic region. This up-regulation was not associated with effects on the numbers of mitotically active progenitors nor differentiated neurones in the preoptic area and in the nuclear recessus posterior of the hypothalamus zebrafish larvae. Furthermore, using a high-throughput video tracking system to monitor locomotor activity in zebrafish larvae, we show that some bisphenol analogues, such as bisphenol AF, significantly reduced locomotor activity following 6 days of exposure. Taken together, our study provides evidence that BPA analogues can also affect the neurobehavioural development of zebrafish.

Sex matters in neuroscience and neuropsychopharmacology.

Prevalence and symptoms of most psychiatric and neurological disorders differ in men and women and there is substantial evidence that their neurobiological basis and treatment also differ by sex. This special issue sought to bring together a series of empirical papers and targeted reviews to highlight the diverse impact of sex in neuroscience and neuropsychopharmacology. This special issue emphasizes the diverse impact of sex in neuroscience and neuropsychopharmacology, including 9 review papers and 17 research articles highlighting investigation in different species (zebrafish, mice, rats, and humans). Each contribution covers scientific topics that overlap with genetics, endocrinology, cognition, behavioral neuroscience, neurology, and pharmacology. Investigating the extent to which sex differences can impact the brain and behavior is key to moving forward in neuroscience research.

Effect of sertraline on central serotonin and hippocampal plasticity in pregnant and non-pregnant rats.

One of the most frequently prescribed selective serotonin reuptake inhibitor medications (SSRIs) for peripartum mood and anxiety disorders is sertraline (Zoloft®). Sertraline can help alleviate mood and anxiety symptoms in many women but it is not known how sertraline, or SSRIs in general, affect the neurobiology of the brain particularly when pregnant. The aim of this study was to investigate how sertraline affects plasticity in the hippocampus, a brain area integral in depression and SSRI efficacy (particularly in males), during late pregnancy and whether these effects differ from the effects of sertraline in non-pregnant females. To do this pregnant and age-matched non-pregnant female Sprague-Dawley rats were used. For the last half of pregnancy (10 days), and at matched points in non-pregnant females, rats were given sertraline (2.5 mg/kg/day or 10 mg/kg/day) or vehicle (0 mg/kg/day). Brains were used to investigate effects on the serotonergic system in the hippocampus and prefrontal cortex and measures of neuroplasticity in the hippocampus. Results show that pregnant females have significantly higher serum levels of sertraline compared to non-pregnant females but that rates of serotonin turnover in the hippocampus and PFC are similar between pregnant and non-pregnant females. Sertraline increased synaptophysin density in the dentate gyrus and CA3 and was associated with a decrease in cell proliferation in the dentate gyrus of non-pregnant, but not pregnant, females. During late pregnancy the hippocampus showed significant reductions in neurogenesis and increases in synaptophysin density. This research highlights the need to consider the unique effect of reproductive state on the neuropharmacology of SSRIs.

Neurodevelopmental effects of natural and synthetic ligands of estrogen and progesterone receptors in zebrafish eleutheroembryos.

Natural and synthetic estrogens and progestins are widely used in human and veterinary medicine and are detected in waste and surface waters. Our previous studies have clearly shown that a number of these substances targets the brain to induce the estrogen-regulated brain aromatase expression but the consequences on brain development remain virtually unexplored. The aim of the present study was therefore to investigate the effect of estradiol (E2), progesterone (P4) and norethindrone (NOR), a 19-nortestosterone progestin, on zebrafish larval neurogenesis. We first demonstrated using real-time quantitative PCR that nuclear estrogen and progesterone receptor brain expression is impacted by E2, P4 and NOR. We brought evidence that brain proliferative and apoptotic activities were differentially affected depending on the steroidal hormone studied, the concentration of steroids and the region investigated. Our findings demonstrate for the first time that steroid compounds released in aquatic environment have the capacity to disrupt key cellular events involved in brain development in zebrafish embryos further questioning the short- and long-term consequences of this disruption on the physiology and behavior of organisms.

Glyphosate and glyphosate-based herbicide exposure during the peripartum period affects maternal brain plasticity, maternal behaviour and microbiome.

Glyphosate is found in a large array of non-selective herbicides such as Roundup® (Monsanto, Creve Coeur, MO, USA) and is by far the most widely used herbicide. Recent work in rodent models suggests that glyphosate-based herbicides during development can affect neuronal communication and result in altered behaviours, albeit through undefined mechanisms of action. To our knowledge, no study has investigated the effects glyphosate or its formulation in herbicide on maternal behaviour and physiology. In the present study, relatively low doses of glyphosate (5 mg kg-1  d-1 ), Roundup® (5 mg kg-1  d-1 glyphosate equivalent), or vehicle were administered by ingestion to Sprague-Dawley rats from gestational day (GD) 10 to postpartum day (PD)22. The treatments significantly altered licking behaviour toward pups between PD2 and PD6. We also show in the dams at PD22 that Roundup exposure affected the maturation of doublecortin-immunoreactive new neurones in the dorsal dentate gyrus of the hippocampus of the mother. In addition, the expression of synaptophysin was up-regulated by glyphosate in the dorsal and ventral dentate gyrus and CA3 regions of the hippocampus, and down-regulated in the cingulate gyrus. Although a direct effect of glyphosate alone or its formulation on the central nervous system is currently not clear, we show that gut microbiota is significantly altered by the exposure to the pesticides, with significant alteration of the phyla Bacteroidetes and Firmicutes. This is the first study to provide evidence that glyphosate alone or in formulation (Roundup) differentially affects maternal behaviour and modulates neuroplasticity and gut microbiota in the mother.

The parental brain and behavior: A target for endocrine disruption.

During pregnancy, the sequential release of progesterone, 17ß-estradiol, prolactin, oxytocin and placental lactogens reorganize the female brain. Brain structures such as the medial preoptic area, the bed nucleus of the stria terminalis and the motivation network including the ventral tegmental area and the nucleus accumbens are reorganized by this specific hormonal schedule such that the future mother will be ready to provide appropriate care for her offspring right at parturition. Any disruption to this hormone pattern, notably by exposures to endocrine disrupting chemicals (EDC), is therefore likely to affect the maternal brain and result in maladaptive maternal behavior. Development effects of EDCs have been the focus of intense study, but relatively little is known about how the maternal brain and behavior are affected by EDCs. We encourage further research to better understand how the physiological hormone sequence prepares the mother's brain and how EDC exposure could disturb this reorganization.

High social motivation induces deficits in maternal behaviour but not plasticity of the subventricular zone in Japanese quail (Coturnix japonica).

Maternal behaviour develops differently depending on the characteristics of an individual, such as age or emotional reactivity. Social motivation, defined as the propensity to establish social contact, has received little attention in relation to maternal behaviour in birds. In addition, the transition to motherhood is a time of plasticity in the brain of the new mother in mammals. However, it remains to be determined how maternal brain plasticity is affected in avian species. The present study investigated how a the social motivation of a mother alters maternal behaviour and brain plasticity of the Japanese quail (Coturnix japonica). Adult females from lines selected for high and low social motivation were exposed to chicks for 11 days. After maternal care testing, and at matched time points in controls, the brains of females were perfused for assessment of doublecortin-immunoreactive staining, a marker of neurogenesis, in the subventricular zone (SVZ), a neurogenic niche. The results obtained showed that high socially motivated female quail spent significantly less time performing maternal behaviour when exposed to chicks compared to low socially motivated females. Moreover, the warming of chicks by high socially motivated females involved less covering postures and mothers were more rejecting of chicks. Interestingly, the plasticity indicators in the SVZ did not differ between low and high socially motivated females and were not associated with differences in maternal caregiving when using doublecortin-immunoreactive staining. Thus, high social motivation in this avian species does not favour maternal behaviour and this level of motivation to the mother is not related to changes in neuroplasticity in the SVZ of the female quail.

Perinatal fluoxetine has enduring sexually differentiated effects on neurobehavioral outcomes related to social behaviors.

Selective serotonin reuptake inhibitor medications (SSRIs) are prescribed to up to 10% of pregnant women to treat maternal mood disorders. Exposure to these medications in-utero has raised concerns about altered neurobehavioral outcomes; most recently those related to peer-to-peer social interactions and play. While clinical data show that both perinatal SSRIs (pSSRI) and maternal stress can contribute to social behavioral changes in children, minimal animal work has investigated the effects of pSSRIs in relevant models of maternal stress or the long-term implications of these effects. Therefore the aim of this work was to investigate the long-term effects of pSSRI exposure to fluoxetine on social behaviors, the hypothalamic pituitary adrenal system (HPA) and hippocampal plasticity in adult male and female rat offspring using a model of pre-gestational maternal stress. Adult Sprague-Dawley female and male rat offspring from the following four groups were utilized: 1. Control + Vehicle, 2. Control + Fluoxetine, 3. Pre-gestational Stress + Vehicle, 4. Pre-gestational Stress + Fluoxetine (n = 8-16/female/age groups, n = 8-14/male/age groups). Main findings show pSSRIs increased social investigation in adult females and increased social play (pouncing, nape attacks) in adult males. Perinatal SSRIs also had sexually differentiated effects on hippocampal neurogenesis and GR density. Pre-gestational stress had enduring effects by decreasing social investigation and hippocampal neurogenesis in adult males. Thus pSSRIs, as well as pre-gestational maternal stress, have significant long-term effects on social neurobehavioral outcomes which differ in males and females. This suggests that it would be valuable to consider fetal-sex specific treatments for maternal mental illness.

Steroid Transport, Local Synthesis, and Signaling within the Brain: Roles in Neurogenesis, Neuroprotection, and Sexual Behaviors.

Sex steroid hormones are synthesized from cholesterol and exert pleiotropic effects notably in the central nervous system. Pioneering studies from Baulieu and colleagues have suggested that steroids are also locally-synthesized in the brain. Such steroids, called neurosteroids, can rapidly modulate neuronal excitability and functions, brain plasticity, and behavior. Accumulating data obtained on a wide variety of species demonstrate that neurosteroidogenesis is an evolutionary conserved feature across fish, birds, and mammals. In this review, we will first document neurosteroidogenesis and steroid signaling for estrogens, progestagens, and androgens in the brain of teleost fish, birds, and mammals. We will next consider the effects of sex steroids in homeostatic and regenerative neurogenesis, in neuroprotection, and in sexual behaviors. In a last part, we will discuss the transport of steroids and lipoproteins from the periphery within the brain (and vice-versa) and document their effects on the blood-brain barrier (BBB) permeability and on neuroprotection. We will emphasize the potential interaction between lipoproteins and sex steroids, addressing the beneficial effects of steroids and lipoproteins, particularly HDL-cholesterol, against the breakdown of the BBB reported to occur during brain ischemic stroke. We will consequently highlight the potential anti-inflammatory, anti-oxidant, and neuroprotective properties of sex steroid and lipoproteins, these latest improving cholesterol and steroid ester transport within the brain after insults.

Perinatal selective serotonin reuptake inhibitor medication (SSRI) effects on social behaviors, neurodevelopment and the epigenome.

Recent research has linked early life exposure to selective serotonin reuptake inhibitor medications (SSRIs) to modifications of social behaviors in children. Serotonin is a key regulator of neurodevelopment, social behaviors and mental health, and with the growing use of SSRIs to treat maternal affective disorders during the perinatal period, questions have been raised about the benefits and risks of perinatal SSRI exposure on the developing child. This review will highlight how perinatal SSRIs affect maternal care and neurodevelopmental outcomes related to social affiliative behaviors in offspring; such as play behaviors, social interactions, reproductive behaviors, and maternal care of the next generation. We will also review how early life exposure to SSRIs can alter related neurobiology, and the epigenome. Both clinical research and findings from animal models will be discussed. Understanding the impact of perinatal SSRIs on neurobehavioral outcomes will improve the health and well-being of subsequent generations.

Perinatal fluoxetine increases hippocampal neurogenesis and reverses the lasting effects of pre-gestational stress on serum corticosterone, but not on maternal behavior, in the rat dam.

There is increasing evidence that mental health concerns, stress-related mental illnesses, and parental stress prior to conception have long-term effects on offspring outcomes. However, more work is needed to understand how pre-gestational stress might affect neurobehavioral outcomes in the mother. We investigated how chronic stress prior to gestation affects maternal behavior and related physiology, and aimed to determine the role that perinatal SSRIs have in altering these stress effects. To do this, female Sprague-Dawley rats were subject to chronic unpredictable stress (CUS) prior to breeding. During the perinatal period they were administered fluoxetine (10mg/kg/day). Four groups of dams were studied: Control+Vehicle, Pre-gestational Stress+Vehicle, Control+Fluoxetine and Pre-gestational Stress+Fluoxetine. Maternal weight, breeding success, and maternal caregiving behaviors were recorded. Measures of serum corticosterone and corticosteroid-binging globulin (CBG) and the number of immature neurons in the dorsal hippocampus were also assessed in the late postpartum. Main findings show pre-gestational stress resulted in poor reproductive success and maintenance of pregnancy. Pre-gestationally stressed dams also showed higher levels of nursing and fewer bouts of licking/grooming offspring in the first week postpartum - behaviors that were not reversed by perinatal fluoxetine treatment. In the dam, perinatal fluoxetine treatment reversed the effect of pre-gestational maternal stress on serum corticosterone levels and increased serum CBG levels as well as neurogenesis in the dorsal hippocampus. Maternal corticosterone levels significantly correlated with blanket and passive nursing. This work provides evidence for a long-term impact of stress prior to gestation in the mother, and shows that perinatal SSRI medications can prevent some of these effects.

Emerging Estrogenic Pollutants in the Aquatic Environment and Breast Cancer.

The number and amount of man-made chemicals present in the aquatic environment has increased considerably over the past 50 years. Among these contaminants, endocrine-disrupting chemicals (EDCs) represent a significant proportion. This family of compounds interferes with normal hormonal processes through multiple molecular pathways. They represent a potential risk for human and wildlife as they are suspected to be involved in the development of diseases including, but not limited to, reprotoxicity, metabolic disorders, and cancers. More precisely, several studies have suggested that the increase of breast cancers in industrialized countries is linked to exposure to EDCs, particularly estrogen-like compounds. Estrogen receptors alpha (ERα) and beta (ERß) are the two main transducers of estrogen action and therefore important targets for these estrogen-like endocrine disrupters. More than 70% of human breast cancers are ERα-positive and estrogen-dependent, and their development and growth are not only influenced by endogenous estrogens but also likely by environmental estrogen-like endocrine disrupters. It is, therefore, of major importance to characterize the potential estrogenic activity from contaminated surface water and identify the molecules responsible for the hormonal effects. This information will help us understand how environmental contaminants can potentially impact the development of breast cancer and allow us to fix a maximal limit to the concentration of estrogen-like compounds that should be found in the environment. The aim of this review is to provide an overview of emerging estrogen-like compounds in the environment, sum up studies demonstrating their direct or indirect interactions with ERs, and link their presence to the development of breast cancer. Finally, we emphasize the use of in vitro and in vivo methods based on the zebrafish model to identify and characterize environmental estrogens.

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.

Selective serotonin reuptake inhibitor medications (SSRIs) are the first lines of treatment for maternal affective disorders, and are prescribed to up to 10% of pregnant women. Concern has been raised about how perinatal exposure to these medications affect offspring neurobehavioral outcomes, particularly those related to social interactions, as recent research has reported conflicting results related to autism spectrum disorder (ASD) risk in children prenatally exposed to SSRIs. Therefore, the aim of this work was to investigate the effects of perinatal exposure to the SSRI fluoxetine on social play behaviors and the hypothalamic pituitary adrenal system, using a model of pre-gestational maternal stress. We also investigated synaptic proteins in the CA2, CA3, and dentate gyrus of the hippocampus, as well as number of immature neurons in the granule cell layer, as both measures of plasticity in the hippocampus have been linked to social behaviors. In pre-adolescent male and female Sprague-Dawley rat offspring, main findings show that perinatal fluoxetine prevents the negative effect of maternal stress on sibling play behavior. However, perinatal fluoxetine increased social aggressive play with a novel conspecific in both sexes and decreased time grooming a novel conspecific in males only. Perinatal fluoxetine also increased serum corticosteroid binding globulin levels, 5-HT levels in the hippocampus, and pre-synaptic density assessed via synaptophysin in the dentate gyrus. Social interaction was significantly correlated with changes in plasticity in the CA2 region of the hippocampus. Pre-gestational maternal stress exposure resulted in significantly decreased rates of hippocampal neurogenesis and synaptophysin density in the dentate gyrus of pre-adolescent males, but not females. Together, these results further characterize the role of perinatal SSRIs, maternal stress prior to conception, and sex/gender on developing social behaviors and related plasticity in the hippocampus of pre-adolescent offspring.