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

目的：内分泌干扰物(EDCs)对高等动物神经发育的研究是一个新的研究领域。关于内分泌细胞在特定基因或动物水平上对神经系统的影响的报道很少。在这项研究中，大鼠、猴子和黑猩猩被用来评估EDCs对神经发育的风险，以推断人类的情况。以大鼠、猴的胎儿、灵长类和啮齿动物的原代神经培养物以及ES细胞作为人类风险评估的模型。研究结果：以大鼠为模型，通过给孕鼠灌胃给药，验证了BPA、NP等雌激素样的EDCs和PCB样的甲状腺激素样的EDCs以及阳性对照药物胺碘酮、硫胺醇、PTU对大鼠胚胎神经发育的影响。神经行为测试在…进行提示雌激素样内皮细胞诱导神经子代，甲状腺激素干扰药物诱导ADHD样行为。这些结果发表在国际期刊上。非人类灵长类胚胎也被用来比较啮齿动物和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，而灵长类胎儿出生时神经发育成熟；2)BPA、甲状腺激素等内分泌细胞在啮齿动物和灵长类动物中的代谢和排异是完全不同的。3)妊娠期BPA与胎儿的母体转运比例不同，妊娠后期胎儿尤其是中枢神经系统的BPA摄取率迅速增加。这些结果表明，简单地将大鼠的数据外推到人类是相对有风险的。以猴胎为模型，TCDD给孕母给药会导致后代出现异常的社会行为，但这些异常在婴儿的发育过程中会减弱。相反，孕妇暴露于双酚A只对男性后代造成严重的性别识别障碍，并在婴儿发育阶段后继续存在。对高剂量接触多氯联苯的母亲所生后代的初步研究表明，对高认知测试(四步指迷宫测试)和甲状腺激素阻滞剂(硫唑)治疗的相对迟缓导致了猴胚胎中枢神经系统的发育不良。所有这些新的结果都是通过本项目获得的，这是EDCs对灵长类神经系统发育的重要清除机制和阈值。下一个目标是我们如何找到这些异常的标记蛋白进行早期诊断，以及我们如何能够避免风险并找到适当的治疗方法来治疗遭受痛苦的儿童。较少

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