NEUROCHEMICAL/BEHAVIORAL/ENDOCRINE EFFECTS OF DEVELOPMENTAL EXPOSURE TO PBCS

接触 PBCS 对发育的神经化学/行为/内分泌影响

• 批准号: 3733764
• 负责人: RICHARD F SEEGAL
• 金额: --
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3733764
• 关键词: chemical structure function; cognition disorders; developmental neurobiology; embryo /fetus toxicology; environmental toxicology; gonadotropins; halobiphenyl /halotriphenyl compound; laboratory rat; milk; neurochemistry; neurotransmitter metabolism; neurotransmitter transport; perinatal; thyroid hormones; thyrotropin; toxin metabolism

In -utero and lactational exposure of humans to polychlorinated biphenyls (PCBs) is associated with cognitive dysfunctions while developmental exposure of laboratory animals to PCBs induces changes in neurotransmitter and cognitive function. Because most laboratory-based and epidemiological studies have investigated the effects of developmental exposure to either mixtures of PCBs or complex environmental samples, it is necessary, in order to understand the mechanisms by which PCBs alter the development and function of the central nervous system, to study the developmental effects of exposure to individual congeners. We propose to determine the neurochemical, neurobehavioral and endocrine effects of in-utero and lactational exposure of the laboratory rat to individual coplanar, di- ortho-substituted and mono-ortho-substituted PCB congeners that we hypothesize will alter neurochemical and second messenger systems and the development of key endocrine systems needed for normal brain development. We will determine; (i) biogenic amine neurotransmitter concentrations in striatal brain slices following in-vitro exposure to these congeners; (ii) regional brain biogenic amine concentrations, circulating concentrations of T3, T4, TSH and circulating gonadotropins in offspring exposed during gestation and lactation to these congeners; (iii) neurochemical, neurobehavioral and endocrine responses in offspring exposed during development to pharmacologic agents and in-vivo generated metabolites (alpha-methyl paratyrosine, NSD-1015, propylthiouracil, catecholestrogens and hydroxybiphenyls) and (iv) changes in cognitive function in animals exposed to PCB congeners and the above agents. These experiments, using a number of prototypical PCB congeners, will allow us to determine which congeners directly affect the development of important neurotransmitters; which congeners indirectly affect brain development by altering key endocrine systems during development and the behavioral consequences of developmental exposure to these congeners. In turn, these data will allow a more complete understanding of the action of complex mixtures of congeners, the risk to the developing human and suggest pharmacologic and behavioral strategies that may ameliorate some of the cognitive dysfunctions observed in developmentally-exposed human infants.

人类宫内和哺乳期对多氯联苯的暴露 (多氯联苯)与发育过程中的认知功能障碍有关 实验动物暴露于多氯联苯引起神经递质的变化 和认知功能。因为大多数基于实验室的和流行病学的 研究已经调查了发育过程中暴露于这两种环境中的任何一种的影响 多氯联苯混合物或复杂的环境样品，是必要的，在 为了了解多氯联苯改变发育和 中枢神经系统的功能，以研究发育的影响 接触到个别同系物的可能性。我们建议确定 宫内和内分泌对神经化学、神经行为和内分泌的影响 实验大鼠哺乳期对个体共面、双平面和双平面的暴露 邻位取代和单邻位取代的多氯联苯同系物 假说将改变神经化学和第二信使系统 大脑正常发育所需的关键内分泌系统的发展。 我们将确定：(I)生物胺类神经递质在 体外暴露于这些同系物后的纹状体脑片；(Ii) 局部脑生物胺浓度，循环中的浓度 接触的子代T_3、T_4、TSH和循环促性腺激素 怀孕和哺乳这些同系物；(Iii)神经化学， 铅暴露对子代神经行为和内分泌反应的影响 药物和体内代谢产物的研究进展 (α-甲基副酪氨酸、NSD-1015、丙基硫氧嘧啶、儿茶酚雌激素 和(Iv)动物认知功能的变化 暴露在多氯联苯同系物和上述制剂中。这些实验使用一个 原型印刷电路板同系物的数量，将使我们能够确定 同系物直接影响重要神经递质的发育； 哪些同系物通过改变键间接影响大脑发育 发育过程中的内分泌系统及其行为后果 发育过程中接触到这些同系物。反过来，这些数据将允许 对复杂混合物的作用有更全面的了解 同系物，对发育中的人类的风险，并建议药理学和 行为策略，可能会改善一些认知 在发育暴露的人类婴儿中观察到的功能障碍。