Article

Sex specific impact of perinatal Bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation.

Department of Biology, North Carolina State University, Raleigh, NC 27695, United States.
NeuroToxicology (Impact Factor: 3.38). 03/2013; 36. DOI: 10.1016/j.neuro.2013.03.001
Source: PubMed

ABSTRACT

Bisphenol A (BPA) is a high volume production chemical used in polycarbonate plastics, epoxy resins, thermal paper receipts, and other household products. The neural effects of early life BPA exposure, particularly to low doses administered orally, remain unclear. Thus, to better characterize the dose range over which BPA alters sex specific neuroanatomy, we examined the impact of perinatal BPA exposure on two sexually dimorphic regions in the anterior hypothalamus, the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the anterioventral periventricular nucleus (AVPV). Both are sexually differentiated by estradiol and play a role in sex specific reproductive physiology and behavior. Long Evans rats were prenatally exposed to 10, 100, 1000, 10000μg/kg bw/day BPA through daily, non-invasive oral administration of dosed-cookies to the dams. Offspring were reared to adulthood. Their brains were collected and immunolabeled for tyrosine hydroxylase (TH) in the AVPV and calbindin (CALB) in the SDN-POA. We observed decreased TH-ir cell numbers in the female AVPV across all exposure groups, an effect indicative of masculinization. In males, AVPV TH-ir cell numbers were significantly reduced in only the BPA 10 and BPA 10000 groups. SDN-POA endpoints were unaltered in females but in males SDN-POA volume was significantly lower in all BPA exposure groups. CALB-ir was significantly lower in all but the BPA 1000 group. These effects are consistent with demasculinization. Collectively these data demonstrate that early life oral exposure to BPA at levels well below the current No Observed Adverse Effect Level (NOAEL) of 50mg/kg/day can alter sex specific hypothalamic morphology in the rat.

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    • "The BPA seems to affect also SDN-POA morphology and function in males, exerting a demasculinizing action on the nucleus. This is confirmed by the reduced number of calbindin-expressing neurons, a reliable marker of SDN- POA borders (McCaffrey et al. 2013). Conversely, BPA is unable to either masculinize the nucleus in females (McCaffrey et al. 2013) or to induce mounting behavior in adult ovariectomized animals primed with testosterone (Naule et al. 2014); rather, it exacerbates the female copulatory behavior, increasing the lordosis quotient in the same animals (Naule et al. 2014). "
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    ABSTRACT: Brain development is an organized, but constantly adaptive, process in which genetic and epigenetic signals allow neurons to differentiate, to migrate, and to develop correct connections. Gender specific prenatal sex hormone milieu participates in the dimorphic development of many neuronal networks. Environmental cues may interfere with these developmental programs, producing adverse outcomes. Bisphenol A (BPA), an estrogenic/antiandrogenic endocrine disruptor widely diffused in the environment, produces adverse effects at levels below the acceptable daily intake. This review analyzes the recent literature on the consequences of perinatal exposure to BPA environmental doses on the development of a dimorphic brain. The BPA interference with the development and function of the neuroendocrine hypothalamus and of the nuclei controlling energy balance, and with the hippocampal memory processing is also discussed. The detrimental action of BPA appears complex, involving different hormonal and epigenetic pathways activated, often in a dimorphic way, within clearcut susceptibility windows. To date, discrepancies in experimental approaches and in related outcomes make unfeasible to translate the available information into clear dose–response models for human risk assessment. Evaluation of BPA brain levels in relation to the appearance of adverse effects in future basic studies will certainly give better definition of the warning threshold for human health.
    Full-text · Article · Jun 2015 · Dose-Response
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    • "While the mechanisms underlying the 31 striking difference in rates and types of behavioral problems across 32 genders are not well studied, laboratory and epidemiological 33 studies suggest that exposure to exogenous endocrine disrupting 34 chemicals during critical windows of brain development may 35 contribute to sex-specific changes in behavior (Paus, 2010; Weiss, 36 2012). 37 Bisphenol A (BPA), an environmental chemical with known 38 estrogenic activity, has been shown to disrupt brain structure and 39 function in laboratory studies (McCaffrey et al., 2013; Richter et al., 40 2007b). These findings are consistent with some studies in humans 41 reporting associations between prenatal maternal BPA and child 42 behavior and executive function (Braun et al., 2009, 2011b; Harley 43 et al., 2013b; Perera et al., 2012). "

    Full-text · Dataset · Nov 2014
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    • "While the mechanisms underlying the 31 striking difference in rates and types of behavioral problems across 32 genders are not well studied, laboratory and epidemiological 33 studies suggest that exposure to exogenous endocrine disrupting 34 chemicals during critical windows of brain development may 35 contribute to sex-specific changes in behavior (Paus, 2010; Weiss, 36 2012). 37 Bisphenol A (BPA), an environmental chemical with known 38 estrogenic activity, has been shown to disrupt brain structure and 39 function in laboratory studies (McCaffrey et al., 2013; Richter et al., 40 2007b). These findings are consistent with some studies in humans 41 reporting associations between prenatal maternal BPA and child 42 behavior and executive function (Braun et al., 2009, 2011b; Harley 43 et al., 2013b; Perera et al., 2012). "
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    ABSTRACT: Prenatal exposure to gonadal hormones plays a major role in the normal development of the male and female brain and sexually dimorphic behaviors. Hormone-dependent differences in brain structure and function suggest that exposure to exogenous endocrine disrupting chemicals may be associated with sex-specific alterations in behavior. Bisphenol A (BPA) is an environmental chemical that has been shown to alter estrogen, androgen, and thyroid hormone signaling pathways. Epidemiological and experimental studies suggest associations between prenatal exposure to BPA and child behavior, however data are inconsistent, and few studies have examined school age children. We examined BPA concentration in spot urine samples from women at mean 27 weeks of pregnancy in relation to child behavior assessed at age 6-10 years using the parent-completed Child Behavior Checklist (CBCL). We report associations between maternal BPA urinary concentrations and several CBCL scores in 153 children (77 boys, 76 girls). We observed a significant interaction between maternal urinary BPA and sex for several behaviors (externalizing, aggression, Anxiety Disorder, Oppositional/Defiant Disorder and Conduct Disorder traits), but no significant associations between BPA and scores on any CBCL scales. However in analyses restricted to children of mothers with detectable prenatal urinary BPA (n=125), BPA was associated with moderately increased internalizing and externalizing behaviors, withdrawn/depressed behavior, somatic problems, and Oppositional/Defiant Disorder traits in boys. In addition we observed a significant interaction between BPA and sex for several behaviors (externalizing, withdrawn/depressed, rule-breaking, Oppositional/Defiant Disorder traits, and Conduct Disorder traits). These results suggest that prenatal exposure to BPA may be related to increased behavior problems in school age boys, but not girls.
    Full-text · Article · Oct 2014 · NeuroToxicology
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