Prenatal Developmental Immunotoxicity of Diethylstilbestrol and Methoxychlor

己烯雌酚和甲氧滴滴涕的产前发育免疫毒性

• 批准号: 8301056
• 负责人: Christine Ann Broussard
• 金额: $ 5.73万
• 依托单位: UNIVERSITY OF LA VERNE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301056
• 关键词: Adult; Affect; Allergic Disease; Apoptosis; Asthma; Atrazine; Atrophic; Autoimmune Diseases; Biological Assay; CD44 gene; Cell Death; Cell Survival; Cells; Chemical Exposure; Child; Communicable Diseases; Consensus; Development; Diethylstilbestrol; Dose; Embryo; Endocrine Disruptors; Environment; Environmental Exposure; Estrogens; Event; Extrinsic asthma; Fetal Development; Flow Cytometry; Fluorescence Microscopy; Food; Genetic; Health; Human; Hypersensitivity; IL2RA gene; Immune; Immune System Diseases; Immune response; Immune system; Immunophenotyping; Immunosuppression; In Vitro; Incidence; Induction of Apoptosis; Infection; Lead; Malignant Neoplasms; Mediating; Membrane; Methoxychlor; Modeling; Nuclear; Pesticides; Pharmacologic Substance; Physical condensation; Plastics; Pregnancy; Propidium Diiodide; Protocols documentation; Research; Role; Self Care; Staging; Staining method; Stains; Systems Development; T cell differentiation; T-Cell Development; T-Lymphocyte Subsets; Time; Vaccination; Vaccines; Woman; annexin A5; antigen challenge; base; bisphenol A; ear infection; exposed human population; fighting; fitness; immune activation; immune function; immunotoxicity; in utero; mature animal; prenatal; prenatal exposure; prevent; reproductive; research study; response; thymocyte

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.

描述（由申请人提供）：内分泌干扰化学品 (EDC) 存在于整个环境中，从废水排放到塑料添加剂，再到粮食作物使用的杀虫剂。越来越多的证据表明，EDC 不仅影响生殖健康和癌症发病率，还影响免疫健康。例如，产前接触多种 EDC 的儿童感染性疾病的发病率增加，并且在受到挑战时疫苗接种反应不佳。此外，在子宫内接触己烯雌酚（一种已知会导致生殖系统癌症的雌激素模型）的女性表现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。由于时间的限制，免疫疾病的迅速增加不能归因于遗传。人们普遍认为，环境暴露，特别是在胎儿发育期间，可能是免疫疾病发生的一个重要因素。尽管越来越多的证据支持 EDC 在免疫系统发育中发挥负面作用，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（妊娠期间）特别脆弱，并且比成人免疫系统更脆弱。我们假设己烯雌酚和甲氧滴滴涕（两种已确定的 EDC）在产前免疫系统发育过程中存在时会改变 T 细胞分化，最终导致不适当的免疫抑制或激活。使用体外产前 T 细胞分化测定，本提案中的实验将确定 DES 和 MXC 1) 是否能够在低剂量的胚胎发育过程中改变免疫系统，2) 通过抑制发育来调节其作用，或 3) 通过诱导细胞凋亡来调节其作用。这种针对 DES 和 MXC 的阶段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，并将成为评估其他 EDC 的产前免疫毒性以及制定预防妊娠期 EDC 暴露引起的免疫疾病的策略的基础。公共卫生相关性：内分泌干扰化学品 (EDC) 存在于整个环境中，从废水排放（例如个人护理产品和药品）到塑料添加剂（例如双酚 A）再到粮食作物使用的杀虫剂（例如莠去津）。越来越多的证据表明，EDC 对免疫系统产生负面影响，可能导致哮喘、过敏、自身免疫性疾病、反复耳部感染和疫苗反应不佳等免疫疾病，尤其是儿童。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 的产前免疫影响以及制定预防因产前 EDC 暴露引起的免疫疾病的策略奠定基础。

项目成果

Methoxychlor metabolite HPTE alters viability and differentiation of embryonic thymocytes from C57BL/6 mice.

• DOI: 10.1080/1547691x.2018.1474978
• 发表时间: 2018-12
• 期刊: Journal of immunotoxicology
• 影响因子: 3.3
• 作者: Leung-Gurung L;Escalante Cobb P;Mourad F;Zambrano C;Muscato Z;Sanchez V;Godde K;Broussard C
• 通讯作者: Broussard C

HPTE-Induced Embryonic Thymocyte Death and Alteration of Differentiation Is Not Rescued by ERα or GPER Inhibition but Is Exacerbated by Concurrent TCR Signaling.

• DOI: 10.3390/ijms221810138
• 发表时间: 2021-09-20
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Avellaneda E;Lim A;Moeller S;Marquez J;Escalante Cobb P;Zambrano C;Patel A;Sanchez V;Godde K;Broussard C
• 通讯作者: Broussard C