PCBs, PBDEs, Hearing Loss & Attention/Impulsivity: Mechanistic Studies in Animals

FRIENDS儿童环境健康中心的总体目标是了解 产前暴露于鱼类中发现的污染物，包括多氯联苯（PCB）， 多溴联苯醚（PBDEs）和甲基汞（MeHg）对认知、运动和听觉的影响 儿童的功能。本提案中描述的动物研究将补充平行的前瞻性研究。 出生队列研究（项目2），其中妇女所生的孩子食用这些污染的鱼 从出生开始就对化学物质进行纵向跟踪。动物研究将使用一种实验性的PCB混合物 这与流行病学研究中妇女食用的鱼类中多氯联苯同系物的情况相似。一 主要目标是阐明多氯联苯和多溴二苯醚对重要执行过程的影响，包括 注意力和抑制控制。哌甲酯和安非他明的药物挑战将决定 常见的ADHD药物治疗改善了暴露于PCB或PBDE的大鼠的表现 注意力和反应抑制测试，以及DA D4和DA D1受体表达的测量， 使用特异性DA D4和DA D1受体激动剂的药物挑战将表明这些受体是否 通路参与调节行为效应。这些研究将与下列研究同时进行： 另一项实验室研究（项目4）将调查多氯联苯和多溴联苯醚暴露对中枢神经系统的影响。 儿茶酚胺的作用以及这些作用通过PCB或PBDE间接介导的程度 对循环甲状腺激素的影响。第二个主要目标是通过 这些多氯联苯会损害耳蜗并导致听力损失。耳蜗的组织学检查将 确定听力障碍是否是由于外毛细胞损伤。减少排放的贡献 循环甲状腺激素或改变ryanodine受体表达在耳蜗中的PCB诱导 将利用两种对甲状腺有相反影响的特定PCB同系物来研究听力损失。 激素和ryanodine通道活性。因为外毛细胞被认为可以抵御噪音 此外，还将进行研究，以确定早期接触PCB是否会增加 在以后的生活中对噪声引起的听力损失的易感性。与过去一样，这些动物研究的结果将 指导选择用于出生队列的结局指标。

The overall goal of the FRIENDS Children's Environmental Health Center is to understand the impact of prenatal exposure to contaminants found in fish-including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and methyl mercury (MeHg)-on cognitive, motor and auditory function of children. The animal studies described in this proposal will complement a parallel prospective birth cohort study (Project 2) in which children born to women consuming fish contaminated with these chemicals will be followed longitudinally from birth. The animal studies will'use an experimental PCB mixture that mimics the PCB congener profile in the fish consumed by women in the epidemiological study. One major goal is to elucidate the effects of PCBs and PBDEs on important executive processes including attention and inhibitory control. Drug challenges with methylphenidate and amphetamine will determine if commonly prescribed ADHD pharmacotherapies improve the performance of PCB- or PBDE-exposed rats on tests of attention and response inhibition, and measures of DA D4 and DA D1 receptor expresion and drug challenges using specific DA D4 and DA D1 receptor agonists will indicate whether these receptor pathways are involved in mediating the behavioral effects. These studies will be conducted in parallel with another laboratory study (Project 4) which will investigate the effects of PCB and PBDE exposure on central catecholamine function and the extent to which these effects are mediated indirectly through PCB or PBDE effects on circulating thyroid hormones. A second major goal is to understand the mechanisms through which PCBs damage the cohclea and produce hearing loss. Histological examinations of the cochlea will confirm whether hearing deficits are due to outer hair cell damage. The contribution of reductions in circulating thyroid hormones or alterations in ryanodine receptor expression in the cochlea to PCB-induced hearing loss will be investigated by utilizing two specific PCB congeners having opposing effects on thyroid hormones and ryanodine channel activity. Because the outer hair cells are believed to protect against noise induced hearing loss, studies will also be conducted to determine if early PCB exposure increases susceptibility to noise-induced hearing loss later in life. As in the past, findings from these animal studies will guide the selection of outcome measures for use in the birth cohort.