Influence of endocrine active compounds on the developing rodent brain

Department of Zoology, North Carolina State University, 127 David Clark Labs, Raleigh, NC 27695, USA.
Brain Research Reviews (Impact Factor: 5.93). 04/2008; 57(2):352-62. DOI: 10.1016/j.brainresrev.2007.06.008
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Changes in the volumes of sexually dimorphic brain nuclei are often used as a biomarker for developmental disruption by endocrine-active compounds (EACs). However, these gross, morphological analyses do not reliably predict disruption of cell phenotype or neuronal function. Therefore, an experimental approach that simultaneously assesses anatomical, physiological and behavioral endpoints is required when developing risk assessment models for EAC exposure. Using this more comprehensive approach we have demonstrated that the disruption of nuclear volume does not necessarily coincide with disruption of cellular phenotype or neuroendocrine function in two sexually dimorphic brain nuclei: the anteroventral periventricular nucleus of the hypothalamus (AVPV) and the sexually dimorphic nucleus of the preoptic area (SDN). These results demonstrate that nuclear volume is likely not an appropriate biomarker for EAC exposure. We further demonstrated that neonatal exposure to the EACs genistein (GEN) and Bisphenol-A (BPA) can affect sexually dimorphic brain morphology and neuronal phenotypes in adulthood with regional and cellular specificity suggesting that effects observed in one brain region may not be predictive of effects within neighboring regions. Finally, developmental EAC exposure has been shown to affect a variety of sexually dimorphic behaviors including reproductive behavior. These effects are likely to have a broad impact as maladaptive behavior could translate to decreased fitness of entire populations. Collectively, these findings emphasize the need to employ a comprehensive approach that addresses anatomical, functional and behavioral endpoints when evaluating the potential effects of EAC exposure.

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Available from: Heather B Patisaul, Jul 28, 2014
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    • "Exposure in utero or perinatally to BPA can lead to permanent behavioral disorders in rodents, including increased levels of aggression and anxiety and alterations in learning, memory, exploration, and emotional responsiveness [55]. Several mouse studies concluded that maternal exposure to low-dose BPA has long-term consequences on neurobehavioral development [56] and neonatal exposure to BPA can affect brain morphology and neuronal adult phenotypes [57]. "
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    ABSTRACT: Phenols are uremic toxins of intestinal origin formed by bacteria during protein metabolism. Of these molecules, p-cresol is the most studied and has been associated with renal function impairment and vascular damage. Bisphenol A (BPA) is a molecule with structural similarity with phenols found in plastic food and beverage containers as well as in some dialyzers. BPA is considered an environmental toxicant based on animal and cell culture studies. Japanese authorities recently banned BPA use in baby bottles based on observational association studies in newborns. BPA is excreted in urine and uremic patients present higher serum levels, but there is insufficient evidence to set cut-off levels or to link BPA to any harmful effect in CKD. However, the renal elimination and potential exposure during dialysis warrant the monitoring of BPA exposure and the design of observational studies in which the potential health risks of BPA for end-stage renal disease patients are evaluated.
    International Journal of Nephrology 07/2013; 2013(114):437857. DOI:10.1155/2013/437857
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    • "We also focused here on males. Fetal exposure of females to BPA leads to a different set of outcomes due to the effects of endogenous estradiol after puberty and the fact that developmental exposure to BPA alters the functioning of the female neuroendocrine system [23] [44]; data from female siblings will be reported elsewhere. "
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    ABSTRACT: Exposure to bisphenol A (BPA) is implicated in many aspects of metabolic disease in humans and experimental animals. We fed pregnant CD-1 mice BPA at doses ranging from 5 - 50,000μg/kg/day, spanning 10-fold below the reference dose to 10-fold above the currently predicted no adverse effect level (NOAEL). At BPA doses below the NOAEL that resulted in average unconjugated BPA between 2-200pg/ml in fetal serum (AUC0-24h), we observed significant effects in adult male offspring: an age-related change in food intake, an increase in body weight and liver weight, abdominal adipocyte mass, number and volume, and in serum leptin and insulin, but a decrease in serum adiponectin and in glucose tolerance. For most of these outcomes non-monotonic dose-response relationships were observed; the highest BPA dose did not produce a significant effect for any outcome. A 0.1-μg/kg/day dose of DES resulted in some but not all low-dose BPA outcomes.
    Reproductive Toxicology 07/2013; 42. DOI:10.1016/j.reprotox.2013.07.017 · 3.23 Impact Factor
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    • "Moreover, depending on the developmental timing of specific brain structures and their coincident exposure to the prevailing steroidal milieu, some brain structures may be demasculinized/defeminized, whereas others are not. In addition, the causes of variations could relate to individual genetic variability or exposure to environmental factors that suppress the reproductive axis (e.g., stress) or disrupt hormone actions (e.g., environmental endocrine disruptors; Ryan and Vandenbergh, 2002; Patisaul and Polston, 2008). This manuscript will review major findings that support the hypothesis that the organizational actions of sex steroids are responsible for sexual differentiation of sexual partner preferences in select non-human species and explore how this work has informed and helped to frame our understanding of biological influences on human sexual orientation and gender identity. "
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    ABSTRACT: The preference to seek out a sexual partner of the opposite sex is robust and ensures reproduction and survival of the species. Development of female-directed partner preference in the male is dependent on exposure of the developing brain to gonadal steroids synthesized during critical periods of sexual differentiation of the central nervous system. In the absence of androgen exposure, a male-directed partner preference develops. The development and expression of sexual partner preference has been extensively studied in rat, ferret, and sheep model systems. From these models it is clear that gonadal testosterone, often through estrogenic metabolites, cause both masculinization and defeminization of behavior during critical periods of brain development. Changes in the steroid environment during these critical periods result in atypical sexual partner preference. In this manuscript, we review the major findings which support the hypothesis that the organizational actions of sex steroids are responsible for sexual differentiation of sexual partner preferences in select non-human species. We also explore how this information has helped to frame our understanding of the biological influences on human sexual orientation and gender identity.
    Frontiers in Endocrinology 10/2011; 2:42. DOI:10.3389/fendo.2011.00042
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