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 产前暴露于鱼类中的污染物--包括多氯联苯(PCBS)、 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。这项建议中描述的动物研究将补充一个平行的预期 出生队列研究(项目2)，妇女食用受这些污染的鱼所生的孩子 化学物质从出生起就会被纵向跟踪。动物研究将使用实验性的多氯联苯混合物 这与流行病学研究中女性食用的鱼中的多氯联苯同系物特征相似。一 主要目标是阐明多氯联苯和多溴二苯醚对重要执行进程的影响，包括 注意力和抑制性控制。扑热息痛和安非他明的药物挑战将决定是否 常用的ADHD药物疗法改善暴露于多氯联苯或多溴二苯醚的大鼠的表现 注意和反应抑制试验及多巴胺D4和多巴胺D1受体表达的测定 使用特定的DA D4和DA D1受体激动剂的药物挑战将表明这些受体 多条通路参与了行为效应的调节。这些研究将与 另一项实验室研究(项目4)，将调查多氯联苯和多溴二苯醚暴露对中央 儿茶酚胺的功能及其通过多氯联苯或多溴二苯醚间接介导的程度 对循环甲状腺激素的影响。第二个主要目标是通过 哪些多氯联苯会损害耳壳并造成听力损失。耳蜗会的组织学检查 确认听力障碍是否由外毛细胞损伤所致。减少对经济的贡献 多氯联苯诱导的循环甲状腺激素或耳蜗兰尼定受体表达的变化 听力损失将通过利用两种对甲状腺有相反影响的特定多氯联苯同系物进行调查。 荷尔蒙和兰诺定通道活性。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多氯联苯是否会增加 在晚年生活中对噪音引起的听力损失的易感性。和过去一样，这些动物研究的结果将 指导选择用于出生队列的结局衡量标准。

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.