Assessment of sex specific endocrine disrupting effects in the prenatal and pre-pubertal rodent brain

Abstract

Background Brain sex differences are found in nearly every region of the brain and fundamental to sexually dimorphic behaviors as well as disorders of the brain and behavior. These differences are organized during gestation and early adolescence and detectable prior to puberty. Endocrine disrupting compounds (EDCs) interfere with hormone action and are thus prenatal exposure is hypothesized to disrupt the formation of sex differences, and contribute to the increased prevalence of pediatric neuropsychiatric disorders that present with a sex bias. Objective Available evidence for the ability of EDCs to impact the emergence of brain sex differences in the rodent brain was reviewed here, with a focus on effects detected at or before puberty. Methods The peer-reviewed literature was searched using PubMed, and all relevant papers published by January 31, 2015 were incorporated. Endpoints of interest included molecular cellular and neuroanatomical effects. Studies on behavioral endpoints were not included because numerous reviews of that literature are available. Results The hypothalamus was found to be particularly affected by estrogenic EDCs in a sex, time, and exposure dependent manner. The hippocampus also appears vulnerable to endocrine disruption by BPA and PCBs although there is little evidence from the pre-pubertal literature to make any conclusions about sex-specific effects. Gestational EDC exposure can alter fetal neurogenesis and gene expression throughout the brain including the cortex and cerebellum. The available literature primarily focuses on a few, well characterized EDCs, but little data is available for emerging contaminants. Conclusion The developmental EDC exposure literature demonstrates evidence of altered neurodevelopment as early as fetal life, with sex specific effects observed throughout the brain even before puberty.

How does sex matter? Behavior, stress and animal models of neurobehavioral disorders

“…Thus BPA exposure during development is able to disrupt sexually dimorphic behaviors in different species by disrupting normal steroid programming of the brain. Numerous studies have confirmed the ability of BPA and other EDs to affect the developing brain in a sex specific way even at very low doses (Patisaul and Polston, 2008;Martini et al, 2010;Cao et al, 2013;Rebuli and Patisaul, 2016). Altogether these findings suggest that when considering any developmental factor, an hypothesis it is not that males and females are more susceptible to a given developmental factor, but rather that developmental factors have sexually dimorphic consequences that need to be accounted for.…”

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

“…Endocrine disruptors, including Bisphenol A and polychlorinated biphenyls , but also dietary phytoestrogens are known to affect neurodevelopment in rodents [163,165] Luteolin and quercetin have been reported to reduce autism symptoms in a small clinical trial [166].…”

Effects of perinatal bisphenol A exposure on the volume of sexually-dimorphic nuclei of juvenile rats: A CLARITY-BPA consortium study

“…BPA has been reported to interfere with the metabolism and signaling of endogenous steroid hormones, particularly estrogen, and numerous studies, including our own, have repeatedly shown in multiple species that developmental exposure to BPA can perturb sexually dimorphic brain development and behavior, even at exposures below the current FDA NOAEL (representative examples include (Braun et al, 2011; Jasarevic et al, 2013; Kinch et al, 2015; Patisaul et al, 2012b; Rebuli and Patisaul, 2015; Sullivan et al, 2014; Wolstenholme et al, 2011)). Although this compounding evidence is compelling, because few published studies are evaluated to be of high utility for human risk assessment, there remains a lack of consensus on the potential risks BPA pose to the developing brain in humans.…”