RESUMO
Arginine vasopressin (AVP) neurons of the hypothalamic paraventricular region (AVPPVN) mediate sex-biased social behaviors across most species, including mammals. In mice, neural sex differences are thought to be established during a critical window around birth ( embryonic (E) day 18 to postnatal (P) day 2) whereby circulating testosterone from the fetal testis is converted to estrogen in sex-dimorphic brain regions. Here, we found that AVPPVN neurons are sexually dimorphic by E15.5, prior to this critical window, and that gestational bisphenol A (BPA) exposure permanently masculinized female AVPPVN neuronal numbers, projections, and electrophysiological properties, causing them to display male-like phenotypes into adulthood. Moreover, we showed that nearly twice as many neurons that became AVP+ by P0 were born at E11 in males and BPA-exposed females compared to control females, suggesting that AVPPVN neuronal masculinization occurs between E11 and P0. We further narrowed this sensitive period to around the timing of neurogenesis by demonstrating that exogenous estrogen exposure from E14.5 to E15.5 masculinized female AVPPVN neuronal numbers, whereas a pan-estrogen receptor antagonist exposed from E13.5 to E15.5 blocked masculinization of males. Finally, we showed that restricting BPA exposure to E7.5-E15.5 caused adult females to display increased social dominance over control females, consistent with an acquisition of male-like behaviors. Our study reveals an E11.5 to E15.5 window of estrogen sensitivity impacting AVPPVN sex differentiation, which is impacted by prenatal BPA exposure.
Assuntos
Compostos Benzidrílicos , Neurônios , Fenóis , Diferenciação Sexual , Animais , Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Feminino , Masculino , Camundongos , Diferenciação Sexual/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Gravidez , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Arginina Vasopressina/metabolismo , Vasopressinas/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Camundongos Endogâmicos C57BL , Estrogênios/metabolismo , Estrogênios/farmacologiaRESUMO
Regulation of physiological homeostasis, including energy balance, is thought to be modified by low levels of adult neurogenesis in the hypothalamus. Hormones such as oestradiol can influence both embryonic and adult hypothalamic neurogenic programs, demonstrating a sensitivity of hypothalamic neural progenitor cells to endogenous hormones. Previously we showed that gestational exposure to environmental levels of the xenoestrogen bisphenol A (BPA) changed neural progenitor cell behaviors in the embryo; however, we did not examine if these changes were permanent to affect adult neurogenesis. Here we investigated whether adult neuro- and/or gliogenesis were altered in mice prenatally exposed to BPA and placed on a high-fat diet challenge. Gestationally exposed adult female mice on a standard diet gained less weight than non-BPA controls, whereas gestationally exposed BPA females on a high-fat diet gained more weight than controls. Males exposed to gestational BPA showed no differences in weight gain relative to control males. Concomitantly, adult neurogenesis was increased in the VMH, DMH, and PVN of adult female mice exposed to BPA on standard diet, suggesting that disrupted adult neurogenesis might perturb normal energy balance regulation in females. These results add to growing evidence that low-dose BPA exposure in utero causes changes to adult hypothalamic function.