Prenatal Developmental Immunotoxicity of Diethylstilbestrol and Methoxychlor

描述（由申请人提供）：内分泌干扰化学品（EDCs）存在于整个环境中，从废水排放到塑料添加剂再到用于粮食作物的农药。越来越多的证据表明，内分泌干扰物不仅影响生殖健康和癌症发病率，还影响免疫健康。例如，出生前暴露于各种内分泌干扰物的儿童感染性疾病的发病率增加，并在受到挑战时产生了次优的疫苗接种反应。此外，子宫内暴露于己烯雌酚（已知导致生殖系统癌症的模型雌激素）的妇女显示出自身免疫性疾病和感染性疾病的增加。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。由于时间的限制，免疫性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。在什么阶段和什么剂量下，人类最容易受到干扰内分泌的化学品的免疫影响？研究表明，发育中的免疫系统（妊娠期间）是独特的脆弱性，比成人免疫系统更脆弱。我们假设，己烯雌酚和甲氧滴滴涕（两个已建立的内分泌干扰物）改变T细胞分化时，存在于产前免疫系统发育，最终导致不适当的免疫抑制或激活。使用体外产前T细胞分化试验，本提案中的实验将确定DES和MXC 1）是否能够在胚胎发育期间以低剂量改变免疫系统，2）是否通过抑制发育介导其作用，或3）是否通过诱导细胞凋亡介导其作用。DES和MXC的这种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的产前免疫毒性和预防妊娠EDC暴露诱导的免疫疾病的策略奠定基础。公共卫生相关性：内分泌干扰化学品（EDCs）存在于整个环境中，从废水排放（例如个人护理产品和药品）到塑料中的添加剂（例如双酚A）再到用于粮食作物的杀虫剂（例如阿特拉津）。越来越多的证据表明，内分泌干扰物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不良，特别是在儿童中。拟议的研究将增强我们对EDC如何以及何时影响免疫系统的理解，并将为评估EDC的产前免疫影响和预防产前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.