Effects of endocrine disrupters on the neuronal development in higher animal species

目的：研究内分泌干扰物对高等动物神经发育的影响是一个新的研究领域。关于EDCs在特定基因或动物水平上对神经系统影响的报道很少。本研究以大鼠、猴子和黑猩猩为研究对象，对EDCs对动物发育的影响进行了风险评估，并对人类进行了外推。大鼠、猴的胎儿、灵长类动物和啮齿动物的原代神经培养物以及胚胎干细胞被用作人类风险评估的模型。擅长研究全身动物的兽医研究人员相互合作，以回答EDCs是否对高等动物的神经发育有不良影响。研究结果：以大鼠为模型，通过给药孕妇，验证雌激素类EDCs如BPA、NP或甲状腺激素类EDCs如PCB及阳性对照药物胺碘酮、噻马索、PTU对大鼠胎儿神经发育的影响。更多的神经行为测试结果表明雌激素类EDCs诱导后代神经紧张，甲状腺激素干扰药物诱导ADHD样行为。这些研究结果发表在国际期刊上。用非人类灵长类动物胎儿比较啮齿类动物与包括人类在内的灵长类动物的差异。结果表明：(1)啮齿动物胎儿出生时神经发育不成熟，而灵长类动物胎儿出生时神经发育成熟。2)啮齿类动物和灵长类动物对双酚a和甲状腺激素等EDCs的代谢和排除完全不同。3)在妊娠期，母体向胎儿传递BPA的比例不同，胎儿尤其是中枢神经系统的摄取比例在妊娠后期迅速增加。这些结果表明，将大鼠数据简单外推到人类身上是相对危险的。以猴胎儿为模型，母体给药TCDD会引起子代社会行为异常，但这些异常在婴儿发育过程中逐渐消失。相反，孕妇暴露于双酚a后，只会导致雄性后代出现严重的性别识别障碍，并且这种异常在婴儿发育阶段后持续存在。对高剂量多氯联苯暴露母鼠所生后代的初步研究表明，高认知测试（四步手指迷宫测试）和甲状腺激素阻滞剂（噻马索）治疗导致猴胎儿中枢神经系统发育不良。本课题的研究获得了新的结果，为EDCs对灵长类神经系统发育的清除机制和阈值提供了重要依据。下一个目标是我们如何找到这些异常的制造蛋白以进行早期诊断，以及我们如何能够避免风险并为受苦的儿童找到合适的治疗方法。少

Purpose : Study of endocrine disrupting chemicals (EDCs) on neural development in higher animals is new research field. There are few reports on effect of EDCs on neural systems at the level of certain gene or animals. In this study, rat, monkey and chimpanzees were used for risk assessment of EDCs on nueral development to extrapolate for humans. Fetuses of rat, monkey, and primary neural cultures of primate and rodents, and ES cells were used as models for human risk assessments. Veterinary researchers being good at whole body animals are collaborate each other to get an answer whether adverse effect of EDCs on neural developments in higher animal species.Research results : Using rat as a model, effects of estrogen like EDCs, such as BPA, NP or thyroid hormone like EDCs such as PCB and positive control drugs i.e., amiodarone, thiamasole, PTU on neural development of rat fetuses were validated by administrating the materials to the pregnant mothers. Nurobehavioral tests were conducted … More and the results suggested that estrogen like EDCs induced nervous offspring and thyroid hormone disturbing drugs induced ADHD like behaviors. These results were published in the international journals.Non human primate fetuses were also used for comparison of the difference of rodents and primate including human being. The results suggested that 1) rodent fetus are born with immature neural development but primate fetus are born with matured neural development at birth stage. 2) Metabolism and exclusion of EDCs such as BPA and thyroid hormone are completely different between rodents and primates. 3) During the stage of pregnancy, ratio of the maternal transfer of BPA to fetus is different and the fetus uptake ratio especially in the CNS was rapidly increased in the later stage of pregnancy. These results suggested that simple extrapolation of rat data to human is relatively risky.Using monkey fetus as a model, TCDD administration to the pregnant mother induced abnormal social behaviors in offspring but these abnormalities were diminished during the development of the infants. On the contrary, BPA exposure of the pregnant mothers resulted in sever sex-identification disorders to only male offspring and its abnormality is continued after developmental stages of the infants. Preliminary studies on offspring delivered from high dose PCB exposed mothers showed relatively retardation to the high cognitive tests (four step finger maze tests) and thyroid hormone blocker (thiamasole) treatments resulted in poor development of the CNS in the monkey fetuses.All these new results were obtained by this projects and it is important clearing mechanism and threshold of EDCs on development of the primate neural systems. The next objectives are how we can find maker proteins of these abnormalities for early diagnosis and how we may be able to avoid the risk and find suitable treatment of the suffering children. Less