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影响是一个新的研究领域。在基因水平或动物水平上研究内分泌干扰物对神经系统的影响的报道较少。在这项研究中，大鼠，猴子和黑猩猩被用来评估内分泌干扰物对神经发育的风险，以推断人类。大鼠、猴的胎儿、灵长类动物和啮齿类动物的原代神经培养物以及ES细胞被用作人体风险评估的模型。研究结果：以大鼠为模型，雌激素类内分泌干扰物（如BPA、NP）或甲状腺激素类内分泌干扰物（如PCB）及阳性对照药物（如苯并三氮唑、苯并三氮唑、苯通过对孕鼠母体给药，验证胺碘酮、甲巯咪唑、PTU对胎鼠神经发育的影响。进行神经行为测试 ...更多信息 提示雌激素样内分泌干扰物可诱导子代神经质，甲状腺激素干扰药物可诱导ADHD样行为。这些结果已在国际期刊上发表，并利用非人灵长类胎儿比较了啮齿类与灵长类包括人类的差异。结果表明：1）啮齿类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BPA和甲状腺激素等内分泌干扰物的代谢和排除是完全不同的。3)在不同妊娠阶段，母体向胎儿转运BPA的比例不同，胎儿摄取BPA的比例在妊娠后期迅速增加，尤其是在中枢神经系统中。这些结果表明，简单地将大鼠的数据外推到人类是相对危险的，以猴胎儿为模型，TCDD给孕母引起后代的异常社会行为，但这些异常在婴儿的发育过程中被减弱。相反，BPA暴露的孕妇导致严重的性别识别障碍，只有男性的后代，其异常是持续发育阶段后的婴儿。对高剂量多氯联苯暴露母猴所产仔猴的初步研究表明，高水平认知能力（四步指迷宫试验）和甲状腺激素阻断剂（硫马索）处理均导致仔猴中枢神经系统发育不良，这些新的结果是本项目所获得的，对阐明内分泌干扰物对灵长类动物神经系统发育的重要清除机制和阈值具有重要意义。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为患病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