scholarly journals X-Linked Histone H3K27 Demethylase Kdm6a Regulates Sexually Dimorphic Differentiation of Hypothalamic Neurons

2021 ◽  
Author(s):  
Lucas E. Cabrera Zapata ◽  
Carla D. Cisternas ◽  
Camila Sosa ◽  
Maria Angeles Arevalo ◽  
Luis Miguel Garcia-Segura ◽  
...  
Keyword(s):  
Sex Differences ◽  
Specific Effect ◽  
Neuronal Cultures ◽  
Sexually Dimorphic ◽  
Mrna Levels ◽  
Estradiol Treatment ◽  
Hypothalamic Neurons ◽  
Gene Encoding ◽  
Genome Wide ◽  
Histone H3k27

Several X-linked genes are involved in neuronal differentiation and may contribute to the generation of sex dimorphisms in brain. Previous results showed that XX hypothalamic neurons grow faster, have longer axons, and exhibit higher expression of the neuritogenic gene neurogenin 3 (Ngn3) than XY before perinatal masculinization. Here we evaluated the participation of candidate X-linked genes in the development of these sex differences, focusing mainly on Kdm6a, a gene encoding for an H3K27 demethylase with functions controlling gene expression genome-wide. We established hypothalamic neuronal cultures from wild-type or transgenic Four Core Genotypes mice, a model that allows evaluating the effect of sex chromosomes independently of gonadal type. X-linked genes Kdm6a, Eif2s3x and Ddx3x showed higher expression in XX compared to XY neurons, regardless of gonadal sex. Moreover, Kdm6a expression pattern with higher mRNA levels in XX than XY did not change with age at E14, P0, and P60 in hypothalamus or under 17β-estradiol treatment in culture. Kdm6a pharmacological blockade by GSK-J4 reduced the expression of neuritogenic genes Neurod1, Neurod2 and Cdk5r1 in both sexes equally, while a sex-specific effect was observed on Ngn3 levels, with a decrease in XX and an increase in XY neurons. Finally, both Kdm6a inhibition and its downregulation using siRNA reduced axonal length only in female neurons, abolishing the sex differences observed in control conditions. Altogether, these results point to Kdm6a as a key mediator of the higher axogenesis and Ngn3 expression observed in XX neurons before critical period of brain masculinization. Keywords: Kdm6a, H3K27 demethylation, sex differences, Ngn3, neuritogenesis, hypothalamic neurons

scholarly journals X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons

2021 ◽  
Author(s):  
Lucas E. Cabrera Zapata ◽  
Carla D. Cisternas ◽  
Camila Sosa ◽  
Luis Miguel Garcia-Segura ◽  
Maria Angeles Arevalo ◽  
...  
Keyword(s):  
Sex Differences ◽  
Specific Effect ◽  
Neuronal Cultures ◽  
Sexually Dimorphic ◽  
Mrna Levels ◽  
Estradiol Treatment ◽  
Hypothalamic Neurons ◽  
Gene Encoding ◽  
Genome Wide ◽  
Histone H3k27

AbstractSeveral X-linked genes are involved in neuronal differentiation and may contribute to the generation of sex dimorphisms in the brain. Previous results showed that XX hypothalamic neurons grow faster, have longer axons, and exhibit higher expression of the neuritogenic gene neurogenin 3 (Ngn3) than XY before perinatal masculinization. Here we evaluated the participation of candidate X-linked genes in the development of these sex differences, focusing mainly on Kdm6a, a gene encoding for an H3K27 demethylase with functions controlling gene expression genome-wide. We established hypothalamic neuronal cultures from wild-type or transgenic Four Core Genotypes mice, a model that allows evaluating the effect of sex chromosomes independently of gonadal type. X-linked genes Kdm6a, Eif2s3x and Ddx3x showed higher expression in XX compared to XY neurons, regardless of gonadal sex. Moreover, Kdm6a expression pattern with higher mRNA levels in XX than XY did not change with age at E14, P0, and P60 in hypothalamus or under 17β-estradiol treatment in culture. Kdm6a pharmacological blockade by GSK-J4 reduced axonal length only in female neurons and decreased the expression of neuritogenic genes Neurod1, Neurod2 and Cdk5r1 in both sexes equally, while a sex-specific effect was observed in Ngn3. Finally, Kdm6a downregulation using siRNA reduced axonal length and Ngn3 expression only in female neurons, abolishing the sex differences observed in control conditions. Altogether, these results point to Kdm6a as a key mediator of the higher axogenesis and Ngn3 expression observed in XX neurons before the critical period of brain masculinization.

scholarly journals Sexually Dimorphic Effect of Genistein on Hypothalamic Neuronal Differentiation in Vitro

2019 ◽  
Vol 20 (10) ◽  
pp. 2465 ◽  
Author(s):  
Marilena Marraudino ◽  
Alice Farinetti ◽  
Maria-Angeles Arevalo ◽  
Stefano Gotti ◽  
GianCarlo Panzica ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Sex Differences ◽  
Estrogen Receptors ◽  
Estrogen Receptor Α ◽  
Neuronal Cultures ◽  
Sexually Dimorphic ◽  
Hypothalamic Neurons ◽  
Estrogen Receptor Antagonists

Developmental actions of estradiol in the hypothalamus are well characterized. This hormone generates sex differences in the development of hypothalamic neuronal circuits controlling neuroendocrine events, feeding, growth, reproduction and behavior. In vitro, estradiol promotes sexually dimorphic effects on hypothalamic neuritogenesis. Previous studies have shown that developmental actions of the phytoestrogen genistein result in permanent sexually dimorphic effects in some behaviors and neural circuits in vivo. In the present study, we have explored if genistein, like estradiol, affects neuritogenesis in primary hypothalamic neurons and investigated the estrogen receptors implicated in this action. Hypothalamic neuronal cultures, obtained from male or female embryonic day 14 (E14) CD1 mice, were treated with genistein (0.1 µM, 0.5 µM or 1 µM) or vehicle. Under basal conditions, female neurons had longer primary neurites, higher number of secondary neurites and higher neuritic arborization compared to male neurons. The treatment with genistein increased neuritic arborization and the number of primary neurites and decreased the number of secondary neurites in female neurons, but not in male neurons. In contrast, genistein resulted in a significant increase in primary neuritic length in male neurons, but not in female neurons. The use of selective estrogen receptor antagonists suggests that estrogen receptor α, estrogen receptor β and G-protein-coupled estrogen receptors are involved in the neuritogenic action of genistein. In summary, these findings indicate that genistein exerts sexually dimorphic actions on the development of hypothalamic neurons, altering the normal pattern of sex differences in neuritogenesis.

scholarly journals Salt-Inducible Kinase Is Involved in the Regulation of Corticotropin-Releasing Hormone Transcription in Hypothalamic Neurons in Rats

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 223-233 ◽  
Author(s):  
Ying Liu ◽  
Victoria Poon ◽  
Graciela Sanchez-Watts ◽  
Alan G. Watts ◽  
Hiroshi Takemori ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Paraventricular Nucleus ◽  
Transcriptional Activation ◽  
Nuclear Translocation ◽  
Primary Cultures ◽  
Luciferase Assay ◽  
Neuronal Cultures ◽  
Mrna Levels ◽  
Hypothalamic Neurons ◽  
Primary Neuronal Cultures

Activation of CRH transcription requires phosphorylation of cAMP response element-binding protein (CREB) and translocation of the CREB coactivator, transducer of regulated CREB activity (TORC) from cytoplasm to nucleus. In basal conditions, transcription is low because TORC remains in the cytoplasm, inactivated by phosphorylation through Ser/Thr protein kinases of the AMP-dependent protein kinases (AMPK) family, including salt-inducible kinase (SIK). To determine which kinase is responsible for TORC phosphorylation in CRH neurons, we measured SIK1 and SIK2 mRNA in the hypothalamic paraventricular nucleus of rats by in situ hybridization. In basal conditions, low mRNA levels of the two kinases were found in the dorsomedial paraventricular nucleus, consistent with location in CRH neurons. One hour of restraint stress increased SIK1 mRNA levels, whereas SIK2 mRNA showed only minor increases. In 4B hypothalamic neurons, or primary cultures, SIK1 mRNA (but not SIK2 mRNA) was inducible by the cAMP stimulator, forskolin. Overexpression of either SIK1 or SIK2 in 4B cells reduced nuclear TORC2 levels (Western blot) and inhibited forskolin-stimulated CRH transcription (luciferase assay). Conversely, the nonselective SIK inhibitor, staurosporine, increased nuclear TORC2 content and stimulated CRH transcription in 4Bcells and primary neuronal cultures (heteronuclear RNA). Unexpectedly, in 4B cells specific short hairpin RNA knockdown of endogenous SIK2 but not SIK1 induced nuclear translocation of TORC2 and CRH transcription, suggesting that SIK2 mediates TORC inactivation in basal conditions, whereas induction of SIK1 limits transcriptional activation. The study provides evidence that SIK represses CRH transcription by inactivating TORC, providing a potential mechanism for rapid on/off control of CRH transcription.

scholarly journals Genomewide Gene-by-Sex Interaction Scans Identify ADGRV1 for Sex Differences in Opioid Dependent African Americans

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Bao-Zhu Yang ◽  
Hang Zhou ◽  
Zhongshan Cheng ◽  
Henry R. Kranzler ◽  
Joel Gelernter
Keyword(s):  
Sex Differences ◽  
Enrichment Analysis ◽  
Inferior Olivary Nucleus ◽  
Sexually Dimorphic ◽  
Genome Wide ◽  
Nominal Significance ◽  
Dsm Iv ◽  
Inferior Olivary ◽  
G Protein Coupled ◽  
Olivary Nucleus

AbstractSex differences in opioid dependence (OD) are genetically influenced. We conducted genomewide gene-by-sex interaction scans for the DSM-IV diagnosis of OD in 8,387 African-American (AA) or European-American subjects (43.6% women; 4,715 OD subjects). Among AAs, 9 SNPs were genome-wide significant at ADGRV1 (adhesion G-protein-coupled receptor V1, lead-SNP rs2366929*(C/T), p = 1.5 × 10−9) for sex-different risk of OD, with the rs2366929*C-allele increasing OD risk only for men. The top co-expressions in brain were between ADGRV1 and GRIK2 in substantia nigra and medullary inferior olivary nucleus, and between ADGRV1 and EFHC2 in frontal cortex and putamen. Significant sex-differential ADGRV1 expression from GTEx was detected in breast (Bonferroni-corrected-p < 0.002) and in heart (p < 0.0125), with nominal significance identified in brain, thyroid, lung, and stomach (p < 0.05). ADGRV1 co-expression and disease-enrichment analysis identifying the top 10 diseases showed strikingly sexually dimorphic risks. The enrichment and transcriptome analyses provided convergent support that ADGRV1 exerts a sex-different effect on OD risk. This is the first study to identify genetic variants contributing to sex differences in OD. It shows that ADGRV1 contributes to OD risk only in AA men, a finding that warrants further study.

scholarly journals The Nuclear Receptor Corepressor Has Organizational Effects within the Developing Amygdala on Juvenile Social Play and Anxiety-Like Behavior

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 1212-1220 ◽  
Author(s):  
Heather M. Jessen ◽  
Mira H. Kolodkin ◽  
Meaghan E. Bychowski ◽  
Catherine J. Auger ◽  
Anthony P. Auger
Keyword(s):  
Gene Expression ◽  
Nuclear Receptor ◽  
Social Play ◽  
Play Behavior ◽  
Sexually Dimorphic ◽  
Mrna Levels ◽  
Estradiol Treatment ◽  
Nuclear Receptor Corepressor ◽  
Males And Females

Nuclear receptor function on DNA is regulated by the balanced recruitment of coregulatory complexes. Recruited proteins that increase gene expression are called coactivators, and those that decrease gene expression are called corepressors. Little is known about the role of corepressors, such as nuclear receptor corepressor (NCoR), on the organization of behavior. We used real-time PCR to show that NCoR mRNA levels are sexually dimorphic, that females express higher levels of NCoR mRNA within the developing amygdala and hypothalamus, and that NCoR mRNA levels are reduced by estradiol treatment. To investigate the functional role of NCoR on juvenile social behavior, we infused small interfering RNA targeted against NCoR within the developing rat amygdala and assessed the enduring impact on juvenile social play behavior, sociability, and anxiety-like behavior. As expected, control males exhibited higher levels of juvenile social play than control females. Reducing NCoR expression during development further increased juvenile play in males only. Interestingly, decreased NCoR expression within the developing amygdala had lasting effects on increasing juvenile anxiety-like behavior in males and females. These data suggest that the corepressor NCoR functions to blunt sex differences in juvenile play behavior, a sexually dimorphic and hormone-dependent behavior, and appears critical for appropriate anxiety-like behavior in juvenile males and females.

Multihormonal regulation of hepatic sinusoidalNtcpgene expression

2004 ◽  
Vol 287 (4) ◽  
pp. G782-G794 ◽  
Author(s):  
Francis R. Simon ◽  
John Fortune ◽  
Mieko Iwahashi ◽  
Ishtiaq Qadri ◽  
Eileen Sutherland
Keyword(s):  
Growth Hormone ◽  
Sex Differences ◽  
Pituitary Hormones ◽  
Male Rats ◽  
Sexually Dimorphic ◽  
Mrna Levels ◽  
Female Rat ◽  
Isolated Rat Hepatocytes ◽  
Hypophysectomized Rats ◽  
Estrogen Administration

Bile acids are efficiently removed from sinusoidal blood by a number of transporters including the Na+-taurocholate-cotransporting polypeptide (Ntcp). Na+-dependent bile salt uptake, as well as Ntcp, are expressed twofold higher in male compared with female rat livers. Also, estrogen administration to male rats decreases Ntcp expression. The aims of this study were to determine the hormonal mechanism(s) responsible for this sexually dimorphic expression of Ntcp. We examined castrated and hypophysectomized rats of both sexes. Sex steroid hormones, growth hormone, thyroid, and glucocorticoids were administered, and livers were examined for changes in Ntcp messenger RNA (mRNA). Ntcp mRNA and protein content were selectively increased in males. Estradiol selectively decreased Ntcp expression in males, whereas ovariectomy increased Ntcp in females, confirming the importance of estrogens in regulating Ntcp. Hypophysectomy decreased Ntcp mRNA levels in males and prevented estrogen administration from decreasing Ntcp, indicating the importance of pituitary hormones. Although constant infusion of growth hormone to intact males reduced Ntcp, its replacement alone after hypophysectomy did not restore the sex differences. In contrast, thyroid hormone and corticosterone increased Ntcp mRNA in hypophysectomized rats. Sex differences in Ntcp mRNA levels were produced only when the female pattern of growth hormone was administered to animals also receiving thyroid and corticosterone. Thyroid and dexamethasone also increased Ntcp mRNA in isolated rat hepatocytes, whereas growth hormone decreased Ntcp. These findings demonstrate the essential role that pituitary hormones play in the sexually dimorphic control of Ntcp expression in adult rat liver and in the mediation of estrogen effects.

Palmitate Induces an Anti-Inflammatory Response in Immortalized Microglial BV-2 and IMG Cell Lines that Decreases TNFα Levels in mHypoE-46 Hypothalamic Neurons in Co-Culture

2018 ◽  
Vol 107 (4) ◽  
pp. 387-399 ◽  
Author(s):  
Stephanie M. Kim ◽  
Emma K. McIlwraith ◽  
Jennifer A. Chalmers ◽  
Denise D. Belsham
Keyword(s):  
Inflammatory Response ◽  
Cell Lines ◽  
Energy Homeostasis ◽  
Saturated Fatty Acids ◽  
Neuronal Cultures ◽  
Mrna Levels ◽  
Hypothalamic Neurons ◽  
Anti Inflammatory ◽  
Inflammatory Profile

Background and Objectives: Elevated levels of saturated fatty acids (SFA) induce a state of neuroinflammation in the hypothalamus. It has been suggested that microglia sense palmitate, a prevalent circulating SFA, and act as mediators of this inflammatory process by communicating with neurons, particularly those involved in appetite regulation. In this study, we examined the inflammatory response to palmitate in immortalized microglial cell lines, BV-2 and IMG, and the subsequent effects on inflammatory gene expression in a model of NPY/AgRP neurons, mHypoE-46. Methods: The BV-2 cells were treated with 50 µM palmitate for 4 and 24 h, and the transcriptional regulation of markers for inflammation and cellular stress was assessed using an RT2 Profiler PCR Array. Select genes were verified with qRT-PCR. The BV-2 and IMG cells were then co-cultured using 1.0-µm cell culture inserts with an immortalized hypothalamic cell line, mHypoE-46, to investigate potential intercellular communication between microglia and neurons. Results: We found that palmitate increased the mRNA levels of specific inflammatory genes, and a general anti-inflammatory profile was revealed in the microglia cells. The mRNA changes in TNFα at 4 and 24 h in BV-2 cells were abrogated with the toll-like receptor 4 (TLR4) inhibitor, TAK-242, indicating the involvement of TLR4. Co-culture of mHypoE-46 neurons with microglia pre-treated with palmitate resulted in repression of TNFα expression in the hypothalamic neurons. As palmitate significantly increased IL-13 expression in microglia, the effect of this cytokine was tested in mHypoE-46 neurons. The addition of IL-13 to neuronal cultures normalized the palmitate-mediated increase in IL-6 and AgRP expression, suggesting that microglia may protect surrounding neurons, at least in part, through the release of IL-13. Conclusions: These results suggest a potential anti-inflammatory role of microglia towards the palmitate-induced neuroinflammation, and potentially energy homeostasis, in hypothalamic neurons.

Abstract MP067: Six Novel Loci With Evidence For Sexual Dimorphism For Human Anthropometric Traits From Genome-wide Meta Analyses Across 270,722 Individuals

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
J C Randall ◽  
T W Winkler ◽  
Z Kutalik ◽  
S I Berndt ◽  
A U Jackson ◽  
...  
Keyword(s):  
Sex Differences ◽  
Sexual Dimorphism ◽  
Sex Difference ◽  
Environment Interaction ◽  
Sexually Dimorphic ◽  
P Values ◽  
Gene Environment ◽  
Genome Wide ◽  
Meta Analyses

Height, adiposity, and fat distribution differ in men and women and, in part, may explain sex differences in susceptibilities to complex diseases like cardiovascular disease. Genome-wide association studies (GWAS) of these traits have previously reported sexually dimorphic associations, yet studies have primarily been limited to interrogation of variants with genome wide significant main effects only. Because of these biological differences by sex and as there is growing interest in the study of gene-environment interactions in the context of GWAS in general, we conducted sex-specific meta-analyses of 9 phenotypes: height (HT), weight (WT), body mass index (BMI), waist circumference (WC), hip circumference (HIP), WC/HC ratio (WHR), WC adjusted for BMI (WCadjBMI), HC adjusted for BMI (HCadjBMI), and WHR adjusted for BMI (WHRadjBMI). In the discovery stage, we performed sex-specific meta-analyses of 46 GWAS, comprising 60,586 men and 73,137 women. Each study used an additive model to test up to ∼2.8M imputed SNPs for association with inverse-normal transformed phenotypes. From our first scan based on the sex-specific association P-values (P women , P men ) across all phenotypes, we selected 619 independent SNPs at a false discovery rate (FDR) of 5% to take forward to replication. We also conducted a second scan based on the P-value for sex difference (P sex-diff ) with better power to detect signals of opposite effect direction, yet we did not detect any signal at FDR of 5%. Follow-up of the 619 SNPs in up to 62,395 men and 74,657 women, many of which were genotyped on Metabochip, a custom Illumina iSelect array to which we submitted sex-specific SNPs, resulted in 205 loci with genome-wide significanct (P women or P men < 5x10 -8 ) p values in the combined discovery and follow-up analysis. For those 205 loci, we found 4 loci with significant (P sex-diff < 0.05/205) and 14 loci with suggestive (P sex-diff <0.05) evidence for sex-difference including known sexually dimorphic associations with anthropometric traits ( GRB14 , 1q41 , VEGFA , ADAMTS9), known anthropometric trait associations without any prior evidence for sexual-dimorphism ( 14q23.1, 3q21.3, 6q14.1, 4q12, 12q24.31, SEC16B, 17q21.32 , and 13q31.3 ), and novel sex-specific associations with anthropometric traits ( 5q11.2, 5q23.1, PPARG, 2q37.1, 17p11.2 , and 5q35.1 ). Interestingly, we found that our replicated loci for WHR/WC were enriched with markers with sex-differences, and that these genetic effects were uniformly stronger in women compared to men. Collectively, these results underscore the gain from sex-stratified GWAS in order to better pinpoint the genetics of complex traits and illustrate a sexually dimorphic genetic underpinning to some of these traits. Our results more globally emphasize the need to consider gene-environment interaction when searching for genes influencing risk to complex disease.

scholarly journals AMBRA1, Autophagy, and the Extreme Male Brain Theory of Autism

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Bernard Crespi ◽  
Silven Read ◽  
Amy Ly ◽  
Peter Hurd
Keyword(s):  
Sex Differences ◽  
Differential Expression ◽  
Genetic Effects ◽  
Sexually Dimorphic ◽  
Male Bias ◽  
Autism Quotient ◽  
Genome Wide ◽  
Extreme Male Brain ◽  
Brain Theory ◽  
Extreme Male Brain Theory

The extreme male brain theory of autism posits that its male bias is mediated by exaggeration of male-biased sex differences in the expression of autism-associated traits found in typical populations. The theory is supported by extensive phenotypic evidence, but no genes have yet been described with properties that fit its predictions. The autophagy-associated gene AMBRA1 represents one of the top genome-wide “hits” in recent GWAS studies of schizophrenia, shows sex-differential expression, and has been linked with autism risk and traits in humans and mice, especially or exclusively among females. We genotyped the AMBRA1 autism-risk SNP in a population of typical humans who were scored for the dimensional expression of autistic and schizotypal traits. Females, but not males, homozygous for the GG genotype showed a significant increase in score for the single trait, the Autism Quotient-Imagination subscale, that exhibits a strong, significant male bias in typical populations. As such, females with this genotype resembled males for this highly sexually dimorphic, autism-associated phenotype. These findings support the extreme male brain hypothesis and indicate that sex-specific genetic effects can mediate aspects of risk for autism.

scholarly journals Sexually dimorphic gene expression and neurite sensitivity to estradiol in fetal arcuate Kiss1 cells

2020 ◽  
Vol 244 (2) ◽  
pp. 273-283
Author(s):  
Caroline Alfaia ◽  
Vincent Robert ◽  
Kevin Poissenot ◽  
Yves Levern ◽  
Daniel Guillaume ◽  
...  
Keyword(s):  
Cell Population ◽  
Primary Cultures ◽  
Developmental Time ◽  
Female Group ◽  
Sexually Dimorphic ◽  
Mrna Levels ◽  
Estradiol Treatment ◽  
Fiber Density ◽  
Functional Studies ◽  
Reproductive Axis

Kiss1 neurons of the arcuate (ARC) nucleus form an interconnected network of cells that communicate via neurokinin B (encoded by Tac2) and its receptor (encoded by Tacr3) and play key roles in the control of the reproductive axis through sex hormone-regulated synthesis and release of kisspeptin peptides (Kp, encoded by Kiss1). The aim of this study was to determine whether the Kiss1 cell population of the ARC already displays sexually dimorphic features at embryonic age E16.5 in mice. At this time of development, Kiss1-GFP- and Kp-immunoreactive cell bodies were restricted to the ARC and not found in the pre-optic area (POA). The Kiss1-GFP cell population was identical in size between sexes but had significantly lower Kiss1, Tac2, and Tacr3 mRNA levels and lower Kp-ir fiber density in the POA in male compared to female fetuses. Receptors for androgen (Ar) and estrogen (Esr1, Esr2, Gpr30) and the Cyp19a1 gene (encoding the estradiol-producing enzyme aromatase) transcripts were also detected in fetal ARC Kiss1-GFP cells with significant sex differences for Ar (higher in males) and Esr1 (higher in females). Functional studies on primary cultures of sorted fetal Kiss1-GFP cells revealed a significant negative effect of estradiol treatment on neurite outgrowth on the fourth day of culture in the female group specifically. We conclude that the ARC Kiss1 cell population is already sexually differentiated at E16.5 and that its morphogenetic development may be particularly vulnerable to estradiol exposure at this early developmental time.

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