Prenatal Developmental Immunotoxicity of Diethylstilbestrol and Methoxychlor

描述（由申请人提供）：内分泌干扰化学物质（EDCs）存在于整个环境中，从废水排放到塑料添加剂到粮食作物上使用的杀虫剂。越来越多的证据表明，EDCs不仅影响生殖健康和癌症发病率，还影响免疫健康。例如，产前暴露于多种EDCs的儿童患传染病的几率增加，在受到挑战时，接种疫苗的反应不理想。此外，在子宫内暴露于己烯雌酚（一种已知会导致生殖癌症的模型雌激素）的妇女显示出自身免疫性疾病和传染病的增加。此外，过敏性疾病和哮喘在过去几十年中有所增加，特别是在儿童中。由于时间限制，免疫疾病的迅速增加不能归因于遗传。普遍的共识是，环境暴露，特别是在胎儿发育期间，可能是免疫疾病发展的一个重要因素。尽管越来越多的证据支持EDC在免疫系统发育中的负面作用，但关键问题仍然存在。在什么阶段和多大剂量的剂量下，人类最容易受到内分泌干扰化学物质的免疫影响？研究表明，发育中的免疫系统（在怀孕期间）是唯一脆弱的，比成人的免疫系统更脆弱。我们假设二乙基雌酚和甲氧基氯（两种已确定的EDCs）在产前免疫系统发育过程中存在时改变T细胞分化，最终导致不适当的免疫抑制或激活。通过体外产前T细胞分化实验，本实验将确定DES和MXC是否能够在低剂量下改变胚胎发育期间的免疫系统，2)通过抑制发育介导其作用，或3)通过诱导细胞凋亡介导其作用。对DES和MXC的阶段特异性分析将增强我们对这些内分泌干扰物如何以及何时影响免疫系统的理解，并将为评估其他EDC的产前免疫毒性以及预防妊娠期EDC暴露引起的免疫疾病的策略奠定基础。公共卫生相关性：从废水排放（如个人护理产品和药品）到塑料添加剂（如双酚A），再到粮食作物上使用的农药（如阿特拉津），环境中到处都存在干扰内分泌的化学物质。越来越多的证据表明，EDCs会对免疫系统产生负面影响，可能导致免疫疾病，如哮喘、过敏、自身免疫性疾病、反复耳部感染和疫苗反应差，尤其是在儿童中。本研究将增强我们对EDCs如何及何时影响免疫系统的理解，并将为评估EDCs的产前免疫影响以及预防产前EDC暴露引起的免疫疾病的策略奠定基础。

DESCRIPTION (provided by applicant): Endocrine-disrupting chemicals (EDCs) are present throughout the environment, from wastewater effluent to additives in plastic to pesticides used on food crops. Growing evidence suggests that EDCs not only influence reproductive fitness and cancer incidence, but also immune fitness. For example, children exposed prenatally to a variety of EDCs had an increased incidence of infectious diseases and mounted a suboptimal vaccination response when challenged. Furthermore, women exposed in utero to diethylstilbestrol (a model estrogen known to cause reproductive cancers) showed an increase in autoimmune and infectious disease. Moreover, allergic diseases and asthma have increased in the past few decades, particularly in children. Because of the time frame, the rapid rise in immune disease cannot be attributed to genetics. The general consensus is that environmental exposures, particularly during fetal development, may be a significant factor in the development of immune disease. Though evidence is mounting that supports a negative role for EDC in immune system development, critical questions remain. At what stage and what doses are humans most vulnerable to the immune impacts of endocrine-disrupting chemicals? Studies have shown that the developing immune system (during gestation) is uniquely vulnerable and more vulnerable than the adult immune system. We hypothesize that diethylstilbestrol and methoxychlor (two established EDCs) alter T cell differentiation when present during prenatal immune system development, ultimately leading to inappropriate immune suppression or activation. Using an in vitro prenatal T cell differentiation assay, the experiments in this proposal will determine whether DES and MXC 1) are capable of altering the immune system during embryological development at low doses, 2) are mediating their effects through inhibition of development, or 3) are mediating their effects through induction of apoptosis. This stage-specific analysis of DES and MXC will enhance our understanding of how and when these endocrine disruptors affect the immune system, and will form the basis for assessment of prenatal immunotoxicity of other EDCs and for strategies to prevent immune disease induced by gestational EDC exposure. PUBLIC HEALTH RELEVANCE: Endocrine-disrupting chemicals (EDCs) are present throughout the environment, from wastewater releases (e.g. personal care products and pharmaceuticals) to additives in plastic (e.g. bisphenol A) to pesticides used on food crops (e.g. atrazine). Growing evidence suggests that EDCs negatively influence the immune system, potentially leading to immune diseases like asthma, allergies, autoimmune disease, repeated ear infections, and poor vaccine responses, particularly in children. The proposed research will enhance our understanding of how and when EDCs affect the immune system, and will form the basis for assessment of prenatal immune impacts of EDCs and for strategies to prevent immune disease caused by prenatal EDC exposure.