砷的内分泌干扰作用T3及RA信号通路及关键调控点研究

Endemic arsenism is a serious health problem in worldwide public health.The key of prevention and control its long-term effects and cancer caused by arsenic exposure is pathogenic mechanism unclear. The recent study proposed that arsenide is a kind of environmental estrogen-like substances. A small number of in vitro studies and our study based-populatin confirmed the potential endocrine disrupting effects of inorganic arsenic,and the health effects caused by arsenic is relationship with abnormal expression of estrogen receptor. However estrogen receptor pathway is difficult to explain the variety of health effects of arsenic. The effects complexity of endocrine disruptors suggest that there may be other receptor signaling pathways, or the various cross-pathways. This study through two different populations: people and animals, applying molecular biology methods to detect the gene and protein changes of T3 signaling pathway and RA signaling pathway, to explore arsenic endocrine disruption and key regulatory point. The study results of arsenic-population would be supported by animal experiments evidence, and to provide a fuller, more comprehensive theoretical basis for the pathogenic mechnism pathway of the endocrine-disrupting effects of arsenic, in the meantime there has important theoretical significance on guiding interventions and prevention of arsenic-induced effects and cancer.

地方性砷中毒是严重危害人体健康的世界性公共卫生问题，制约防治其远期效应及癌症的关键是砷中毒致病机理不清。最新研究提出砷化物是一类环境雌激素样物质，以往少数体外研究及我们的人群研究证实了无机砷具有潜在的内分泌干扰效应，砷引起的健康效应与雌激素受体的异常表达有关，然而，雌激素受体途径难以解释砷的多种健康效应问题。内分泌干扰作用的复杂性提示可能存在其他受体信号通路，或是各种通路的交错作用。本研究拟通过人群和动物两个不同种群的研究，应用分子生物学方法，以T3信号通路和RA信号通路相关基因、蛋白的改变为切入点，探讨砷的内分泌干扰作用及关键调控点，该研究以动物实验佐证人群研究，为砷的内分泌干扰效应致病机理的作用途径提供更充实、更全面的理论依据，同时对于探讨砷暴露人群有效的干预措施和可行性、预防砷诱导的远期效应及肿瘤的发生具有重要的理论指导意义。

地方性砷中毒是严重危害人体健康的世界性公共卫生问题，制约防治其远期效应及癌症的关键是砷中毒致病机理不清。最新研究提出砷化物是一类环境雌激素样物质，以往少数体外研究及我们的人群研究证实了无机砷具有潜在的内分泌干扰效应，砷引起的健康效应与雌激素受体的异常表达有关，然而，雌激素受体途径难以解释砷的多种健康效应问题。本项目进行了人群和动物两个不同种群的研究，从人群分子流行病学进一步证实了砷具有内分泌干扰效应，可以通过影响THRs、HSP、RARs 和RXRs这些核受体介导的各种信号通路，及各种通路的交错作用，形成复杂的交通网影响机体的各个系统器官，造成砷暴露人群近期及远期的各种影响或疾病。动物研究结果提示砷引起的皮肤损伤可能与维甲酸上调AQP3有关，随着暴露时间的延长，砷对大鼠MR和维甲酸可产生一定影响，由于MR和维甲酸对机体生长、分化及代谢方面具有重要作用，提示砷可能通过其发挥效应。本项目的人群及动物研究结果为砷的内分泌干扰效应的作用途径与机制进一步提供了更充实、更全面的结果及理论依据。该结果对于探讨饮水型砷暴露人群有效的干预措施和可行性、预防砷诱导的远期效应及肿瘤的发生具有重要的理论指导意义。