Mechanisms of Reproductive Neuroendocrine Toxicity

描述(申请人提供)：拟议研究的长期目标是确定神经内分泌紊乱的主要原因和公共卫生关注的主要环境污染物的目标。在这一续篇提案中，将在大西洋鱼模型中研究Aroclor 1254(多氯联苯)导致色氨酸羟基酶(TPH)活性受损的近端原因及其生殖神经内分泌后果。将在大黄鱼身上检验以下总体假设：多氯联苯引起的5-羟色胺-促性腺激素释放激素-黄体生成素(5-羟色胺-促性腺激素释放激素-黄体生成素)控制生殖的神经内分泌途径的损害涉及非共面同系物诱导的TPH活性下降，这是氧化作用/损害的结果。首先，将研究一系列多氯联苯浓度对TPH活性和下丘脑TPH蛋白及其mRNA水平的影响，然后进行实验，以调查氧化损伤和神经内分泌中断之间的关系。随后，将研究维生素E(一种抗氧化剂)对5-羟色胺能功能的影响，以及它在逆转多氯联苯对脂质过氧化、丙二醛-蛋白加合物形成、TPH活性和神经内分泌功能影响方面的效果。最后，将比较共面二恶英类多氯联苯同系物(PCB77)与两个非共面二邻位取代多氯联苯同系物(PCB47和PCB153)对TPH活性的影响，以确定多氯联苯混合物中神经毒性效应的可能致病因素。多氯联苯引起的下丘脑5-羟色胺能功能损害对5-羟色胺-促性腺激素释放激素-黄体生成素神经内分泌系统的功能完整性的影响也将被调查。其具体目标是：i)确定多氯联苯引起的下丘脑TPH活性下降是否伴随着TPH蛋白和mRNA水平的变化；ii)确定多氯联苯引起的TPH活性和5-羟色胺促性腺激素释放激素功能下降是否与氧化损伤有关，以及抗氧化剂逆转这些影响的有效性；iii)确定多氯联苯混合物中的非共面二邻位取代多氯联苯同系物是否可以解释其对TPH活性和5-羟色胺促性腺激素释放激素功能的毒性影响。现在有令人信服的证据表明，在五大湖环境或职业暴露于多氯联苯或食用受多氯联苯污染的鱼与人类生殖和神经内分泌功能障碍及其子女的发育缺陷有关。然而，多氯联苯的神经毒性机制仍然知之甚少。这项拟议的研究将探索多氯联苯神经毒性和神经内分泌毒性的新机制，这可能对其他神经功能也有意义，如与心理健康相关的功能。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to determine the principal causes of neuroendocrine disruption and targets of the major environmental contaminants of public health concern. In this continuation proposal the proximal cause of Aroclor 1254 (PCB)-induced impairment of tryptophan hydroxylase (TPH) activity and the reproductive neuroendocrine consequences will be investigated in a fish model, Atlantic croaker. The following overall hypothesis will be tested in croaker: PCB-induced impairment of the serotonin-gonadotropin releasing hormone-luteinizing hormone (5-HT-GnRH-LH) neuroendocrine pathway controlling reproduction involves a non-coplanar congener-induced decrease in TPH activity, which is the result of oxidative effects/damage. Initially, the effects of a range of PCB concentrations on TPH activity and hypothalamic levels of the TPH protein and its mRNA will be investigated followed by experiments to investigate associations between oxidative damage and neuroendocrine disruption. Subsequently, the effects of vitamin E (an antioxidant) treatment on serotonergic functions, and its efficacy in reversing the effects of the PCB on lipid peroxidation, malondialdehyde-protein adduct formation, TPH activity, and neuroendocrine function, will be investigated. Finally, the effects of a coplanar dioxin-like PCB congener (PCB 77) on TPH activity will be compared to those observed with two non-coplanar di-ortho-substituted PCB congeners (PCB 47 and PCB 153) to identify likely causative agents of the neurotoxic effects in the PCB mixture. The consequences of PCB congener-induced impairment of hypothalamic serotonergic function on the functional integrity of the 5-HT-GnRH-LH neuroendocrine system will also be investigated. The specific objectives are to: i) determine whether the PCB-induced decrease in the hypothalamic TPH activity is accompanied by alterations in TPH protein and mRNA levels; ii) determine whether the PCB-induced decreases in TPH activity and 5-HT-GnRH-LH function are associated with oxidative damage, and the efficacy of an antioxidant in reversing these effects; iii) determine whether the non-coplanar di-ortho-substituted PCB congener component of PCB mixtures could account for their toxic effects on TPH activity and 5-HT-GnRH-LH function. There is now compelling evidence that the environmental or occupational exposure to PCBs or consumption of PCB-contaminated fish in the Great Lakes is associated with reproductive and neuroendocrine dysfunction in humans and developmental deficits in their children. However, the mechanisms of PCB neurotoxicity remain poorly understood. The proposed study will investigate a novel mechanism of PCB neurotoxicity and neuroendocrine toxicity which may also have significance for other neural functions such as those associated with mental health.