Endocrine Disrupting Chemicals and Male-biased Neurobehavioral Disorders

儿童神经发育障碍（NDD），如注意力缺陷/多动障碍（ADHD）和 自闭症谱系障碍（ASD）具有巨大的社会，经济和个人后果。的 这些疾病的发病率和行为表现因遗传性别而异，男性偏好。而 已经报告了这种男性偏倚的多因素风险，但机制性起源仍未得到解决。 越来越多的流行病学和动物研究确定了内分泌干扰物（EDCs）的作用。 暴露在儿童NDD病因中的作用。然而，转换风险是困难的，因为幼儿期 暴露越来越多地以低剂量暴露于内分泌干扰物的混合物为特征，例如 最近的一项研究发现，90%的新生儿血清中的双酚a（BPA）和 全氟辛酸（PFOA）。我们以前的数据利用了一种精心策划的内分泌干扰物混合物（MIX）， 这些婴儿暴露的代表，发现低剂量EDC混合物改变了睾丸激素（T）水平， 雄性小鼠在出生时，并导致男性特有的行为变化，包括减少注意力，冲动， 以及社交能力下降，这是多动症和自闭症的表现型。在啮齿动物和人类中，雄性 在出生前后不久经历T激增，这对神经系统发育至关重要。我们 数据表明，出生时的T可能是多种EDC混合物的敏感靶点。MIX曝光率也很低 男性中DNA甲基转移酶（DNMT 1）水平降低和低甲基化敏感印迹基因 纹状体，一个对这些行为域至关重要的区域。DNA甲基化谱受多种因素的影响。 内分泌干扰物，并建议作为一个潜在的机制，内分泌干扰物赋予的风险。因此，本提案将 研究一种假设的机制途径，将EDC诱导的出生时T水平升高与DNA 纹状体低甲基化作为性别依赖性行为缺陷机制这一假设将是 在一系列的3个目标中进行了检查，这些目标系统地操纵内分泌和表观遗传信号， 和行为功能进入成年期。首先，它将测试新生儿T给药的能力， MIX EDC暴露的表观遗传和行为后果。此外，EDC诱导的 通过DNMT抑制的DNA低甲基化将使用具有以下特征的遗传修饰小鼠品系进行测试： DNMT 1活性降低。因为大脑发育的表观遗传机制是高度区域化和细胞类型化的 具体来说，我们以前的评估使用整个纹状体，拟议的目标将调查全基因组DNA 来自腹侧纹状体的神经元的甲基化谱。作为向前迈出的重要一步，该提案将纳入 翻译行为分析和先进的表观遗传技术，以告知我们的理解，男性 易损性.围产期T峰是EDC神经毒性的一个研究不足的目标。拟议的研究将 显著扩展了我们对EDC混合物如何改变性别依赖性CNS发育的有限知识， 这将为风险评估和公共卫生保护提供必要的新数据。

Children’s neurodevelopmental disorders (NDDs), such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASDs), have tremendous societal, economic, and personal consequences. The incidence rates and behavioral presentation of these disorders vary by genetic sex, with a male bias. While multifactorial risks have been reported for this male bias, the mechanistic origins remain unresolved. Increasingly, epidemiological and animal studies identify a role for endocrine disrupting chemical (EDCs) exposures in the etiology of children’s NDDs. However, translating risk is difficult because early childhood exposures are increasingly characterized by low dose exposures to mixtures of EDCs, as exemplified by a recent study that found 90% of newborn children had measurable serum levels of both bisphenol-a (BPA) and perfluorooctanoic acid (PFOA) at birth. Our previous data utilizing a curated mixture (MIX) of EDCs, representative of these infant exposures, found that a low dose EDC mixture altered testosterone (T) levels in male mice at birth and resulted in male-specific behavioral changes, including reduced attention, impulsivity, and reduced sociability, phenotypes seen in ADHD and ASDs. Occurring in both rodents and humans, males experience a surge of T shortly before and after birth that is essential for nervous system development. Our data indicate that T at birth may be a sensitive target of multiple EDC mixtures. MIX exposure also marginally reduced DNA methyltransferase (DNMT1) levels and hypomethylated sensitive imprinted genes in male striatum, a region essential for these behavioral domains. DNA methylation profiles are influenced by various EDCs and suggested as a potential mechanism by which EDCs confer risk. Consequently, this proposal will investigate a hypothesized mechanistic pathway linking EDC-induced elevated T levels at birth with DNA hypomethylation in striatum as a mechanism of sex-dependent behavioral deficits. This hypothesis will be examined in a series of 3 Aims that systematically manipulate endocrine and epigenetic signals and track brain and behavioral function into adulthood. First, it will test the ability of neonatal T administration to phenocopy both the epigenetic and behavioral consequences of MIX EDC exposure. In addition, the role of EDC-induced DNA hypomethylation via DNMT inhibition will be tested using a genetically modified strain of mice with reduced DNMT1 activity. Because epigenetic mechanisms of brain development are highly region and cell-type specific, and our prior assessments used whole striatum, the proposed aims will investigate genome-wide DNA methylation profiles in neurons from ventral striatum. As an essential step forward, this proposal will integrate translational behavioral assays and advanced epigenetic techniques to inform our understanding of male vulnerability. The perinatal T surge is an understudied target of EDC neurotoxicity. The proposed studies will significantly expand our limited knowledge of how EDC mixtures alter CNS development in a sex-dependent fashion and will provide new data that are essential for risk assessment and public health protection.