Analysis for the mechanisms affecting neural of development by endocrine disrupting chemicals using non-human primates

考虑到在进行内分泌干扰物对人类的风险评估时的物种差异，实验中使用了与人类关系密切的非人类灵长类动物。根据前人的研究结果，双酚A被用作雌激素类药物，他巴唑被用来替代具有抑制甲状腺激素作用的多氯联苯或TCDD。对雄性和雌性子代组成的双酚A处理组进行了脑性二形核的蛋白质组分析。暴露组雄鼠表现为雌性模式，暴露组雌性动物倾向于中性模式。针对与对照组有显著差异的多肽斑点，研究暴露组的性别差异。用免疫组织化学方法检测了覆盖靶点的几种蛋白质在暴露组和对照组中的性别差异，但发现对照性别差异或暴露效应之间的差异是…在形态上更加困难。今后应进行包括激素受体在内的定量分析。甲硫咪唑给药实验发现，严重影响胎儿甲状腺激素的产生和非人类灵长类动物的大脑发育。并对他巴唑的作用机理进行了实验研究。在怀孕的不同阶段(怀孕早期、中期、晚期和末期)，母亲服用他巴唑，并对从个体获得的后代胎儿大脑进行精确分析。末期(孕期130至150天的剂量)处理的影响最大。因此，在此基础上进行了新的实验，增加了四个个体，以获得可重复性的结果。用Western印迹分析定量分析候选蛋白表达的变化。暴露组的甲状腺肿大和功能障碍具有明显的重复性，但在神经元发育方面，蛋白质表达水平的个体差异很大。暴露组大神经元投射有延迟的趋势，但无显着性差异。在个体中，甲状腺激素浓度与甲状腺增大和神经发育迟缓之间的相关性并未显示出明显的关系。与其他神经细胞相比，小脑中的浦肯野细胞和大脑皮层中的锥体细胞显示出强烈的影响。通过对个体的定量分析，认为有必要进行针对这些细胞的实验。较少

Consideration of species differences in conducting risk assessments of endocrine disrupting chemicals to humans, closely related non-human primates were used in experiments. Bisphenol A was used as an estrogenic agents from the results of previous studies, and methimazole was conducted as an alternative of the PCB or TCDD which have the effect of inhibiting thyroid hormones. Bisphenol A treated groups consisting of male and female offspring were done in proteome analysis for sexually dimorphic nucleus of the brain. Exposure group of male exhibited female patterns, and exposed females tended to show neutral patterns. Peptide spots showing significant differences from the control group were targeted, and sex differences in the exposed group were studied. Several proteins covering the targeted spots were examined by immunohistochemical methos in both exposure and control groups for sex differences, however, to find the difference between the control sex difference or exposure effects were … More difficult morphologically. The quantitative analysis should be carried, including hormone receptors in the future. Methimazole administration experiments were found to affect severely both fetal thyroid hormone production and brain development in non-human primates. The experiments to elucidate the mechanisms of methimazole were proceeded. During different stages of pregnancy (early pregnancy, mid, late, and end stages) mothers were administered methimazole and the offspring fetal brain obtained from individuals were analyzed precisely. Terminal phase (doses from the 130 to 150 days in gestation) treatments influenced the strongest effect. Thus, new experiment was proceeded to add four more individuals to obtain reproducible results based on this. Quantitative analysis of changes in the expression of candidate proteins by Western blot analysis. Thyroid enlargement and dysfunction were observed in the exposed group with a clear reproducibility, however, as for neuronal development, individual differences in protein expression level were strong. A tendency of retardation in large neural cell projections in the exposed group was observed but there was no significant difference. A correlation between thyroid hormone concentrations with enlarging thyroid glands and neural developmental retardations in individuals did not reveal a clear relationship. Purkinje cells in the cerebellar and pyramidal cells in the cerebral cortex showed a strong impact by exposure compared to other neural cells. An experiment targeted to these cells was considered necessary by quantitative analysis of individual in the future. Less