Endocrine Disrupting Chemicals and Male-biased Neurobehavioral Disorders

儿童神经发育障碍(NDDS)，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。这个 这些疾病的发病率和行为表现因遗传性别而异，男性偏向。而当 这种男性偏见的多因素风险已有报道，但其机制起源仍未解决。 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 儿童NDDS的病因学暴露。然而，将风险转化为风险是困难的，因为儿童早期 暴露的特征越来越多地表现为低剂量暴露于EDCs混合物，例如 最近的一项研究发现，90%的新生儿血清双酚A(BPA)和 出生时的全氟辛酸(PFOA)。我们之前的数据使用了经过精选的EDC混合物(混合)， 研究发现，低剂量的EDC混合物改变了婴儿体内的睾酮(T)水平。 雄性小鼠出生时，导致雄性特有的行为变化，包括注意力减少，冲动， 社交能力降低，这是ADHD和ASD的表型。在啮齿动物和人类中都发生，雄性 在出生前和出生后不久，经历T的激增，这对神经系统发育是必不可少的。我们的 数据表明，出生时的T可能是多种EDC混合物的敏感靶点。混合暴露也略微 男性DNA甲基转移酶(DNMT1)水平降低与敏感印迹基因去甲基化 纹状体，这是这些行为区域必不可少的区域。DNA甲基化特征受多种因素的影响 并建议将其作为一种潜在的风险传递机制。因此，这项提议将 研究EDC诱导的出生时T水平升高与DNA之间的假想机制途径 纹状体低甲基化是性别依赖性行为缺陷的一种机制。这一假设将是 通过系统地操纵内分泌和表观遗传信号并跟踪大脑的一系列3个目标进行检查 和行为功能进入成年期。首先，它将测试新生儿T细胞的表型复制能力 混合EDC暴露的表观遗传和行为后果。此外，EDC诱导的作用 通过抑制DNMT的DNA低甲基化将使用一种转基因小鼠进行测试 DNMT1活性降低。因为大脑发育的表观遗传机制是高度区域性和细胞型的 具体来说，我们先前的评估使用了整个纹状体，拟议的目标将研究全基因组dna。 腹侧纹状体神经元的甲基化特征。作为向前迈出的重要一步，这项提议将把 翻译行为分析和先进的表观遗传学技术有助于我们了解男性 脆弱性。围产期T波是EDC神经毒性的一个研究不足的靶点。拟议的研究将 极大地扩展了我们关于EDC混合物如何改变性别依赖患者中枢神经系统发育的有限知识 并将提供对风险评估和公共卫生保护至关重要的新数据。

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.