Developmental immunotoxicity induced by prenatal cadmium exposure

产前镉暴露引起的发育免疫毒性

基本信息

批准号：
9199085
负责人：
John B Barnett
金额：
$ 37.5万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9199085
关键词：
14 year old Address Adoptive Transfer Adult Affect Age Animals Antibodies Antibody Formation Antibody Response Area Autoimmune Diseases Autoimmune Process Binding Biological Assay Birth Body Burden C57BL/6 Mouse Cadmium Carcinogens Cell physiology Cells Child Cigarette Communities Coupled Data Development East Germany Embryonic Development Epidemiology Exhibits Exposure to FOXP3 gene Family Felis catus Female Funding Generations Growth Half-Life Heavy Metals Hour House Dust Human IL2RA gene Immune Immunization Immunize Inbred NOD Mice Insulin-Dependent Diabetes Mellitus Laboratory Study Lead Link Measures Methylation Mothers Mus Newborn Infant Pathology Pathway interactions Penetrance Peripheral Plants Play Postpartum Period Predisposition Pregnancy Production Regulatory T-Lymphocyte Request for Applications Role Schools Smoking Splenocyte Testing Thymocyte Development Time Vaccines WNT Signaling Pathway Water Work Xenobiotics Zinc epidemiology study experimental study exposed human population exposure pathway immunoregulation immunotoxicity in utero mRNA Expression manufacturing facility member mouse model offspring postnatal prenatal prenatal exposure public health relevance response superfund site thymocyte transcription factor tumor

14 year old Address Adoptive Transfer Adult Affect Age Animals Antibodies Antibody Formation Antibody Response Area Autoimmune Diseases Autoimmune Process Binding Biological Assay Birth Body Burden C57BL/6 Mouse Cadmium Carcinogens Cell physiology Cells Child Cigarette Communities Coupled Data Development East Germany Embryonic Development Epidemiology Exhibits Exposure to FOXP3 gene Family Felis catus Female Funding Generations Growth Half-Life Heavy Metals Hour House Dust Human IL2RA gene Immune Immunization Immunize Inbred NOD Mice Insulin-Dependent Diabetes Mellitus Laboratory Study Lead Link Measures Methylation Mothers Mus Newborn Infant Pathology Pathway interactions Penetrance Peripheral Plants Play Postpartum Period Predisposition Pregnancy Production Regulatory T-Lymphocyte Request for Applications Role Schools Smoking Splenocyte Testing Thymocyte Development Time Vaccines WNT Signaling Pathway Water Work Xenobiotics Zinc epidemiology study experimental study exposed human population exposure pathway immunoregulation immunotoxicity in utero mRNA Expression manufacturing facility member mouse model offspring postnatal prenatal prenatal exposure public health relevance response superfund site thymocyte transcription factor tumor

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项目摘要

DESCRIPTION (provided by applicant): Cadmium is a heavy metal and carcinogen that is present at superfund sites, in battery manufacturing facilities, in and around zinc smelters, and in cigarettes (the most common exposure pathway). An epidemiological study of 5- to 14-year-olds in a heavily Cd-contaminated area indicated a high correlation between Cd exposure and immunomodulation1. Although the mothers of these children were likely carrying a heavy Cd body burden during the gestation of their children, the direct effects of prenatal exposure (as opposed to postnatal exposure) on measured immunomodulation cannot be distinguished-an important consideration, since the postnatal effects of prenatal and adult exposure to xenobiotics often differ markedly. Prenatal exposure of C57Bl/6 mice to Cd causes reduced regulatory T cell (Treg) numbers and markedly increased antibody (Ab) in female offspring up to 20 weeks of age. Wnt levels are also markedly reduced2 and Wnt signaling has been linked to Treg cell production and stability. Thus, we will test the hypothesis that prenatal Cd exposure decreases Wnt signaling that results in decreased Treg cell function and subsequently, increased Ab production. The limited epidemiological evidence, coupled with our laboratory studies using mice, imply that the probable immune consequences of prenatal Cd exposure are cause for alarm. The study we propose will address the overall hypothesis that prenatal exposure to Cd reduces regulatory T cell (Treg) function resulting in marked increases in antibody (Ab) which may lead to a higher propensity to developing autoimmune disease or reduced tumor surveillance. It comprises three aims: Aim 1: Determine the Effect of Prenatal Cd Exposure on T Regulatory Cells; Aim 2: Determine the Role Decreased Wnt10b Activity in CdTx Newborn Offspring Plays in Thymocyte Development; and, Aim 3: Determine the Potential for CdTx Offspring to Exhibit Exacerbated Autoimmune-Induced Pathology due to Increased Ab Production.

描述（由申请人提供）：镉是一种重金属和致癌，在超级基金地点，电池制造设施，锌冶炼厂及其周围以及香烟（最常见的暴露途径）中存在。在cd污染的重度污染区域中对5至14岁儿童的流行病学研究表明，CD暴露与免疫调节之间存在很高的相关性。尽管这些孩子的母亲在孩子的妊娠期间可能会承受沉重的CD体重负担，但产前暴露（与产后暴露相反）对测量的免疫调节的直接影响无法区分重要的考虑因素，因为产前和成人对Xenobiotics的暴露后的影响通常不同。 C57BL/6小鼠对CD的产前暴露会导致调节性T细胞（Treg）数量减少，并在20周龄大的女性后代中显着增加抗体（AB）。 WNT水平也显着降低2，Wnt信号传导已与Treg细胞的产生和稳定性联系在一起。因此，我们将测试以下假设：产前CD暴露会降低Wnt信号传导，从而导致Treg细胞功能降低，然后随后增加AB产生。有限的流行病学证据，再加上我们使用小鼠的实验室研究，这意味着产前CD暴露的可能免疫后果引起了警报。我们提出的研究将解决总体假设，即在产前暴露CD会降低调节性T细胞（TREG）功能，从而导致抗体显着增加（AB），这可能会导致更高的倾向于发展自身免疫性疾病或降低肿瘤监测。它包括三个目的：目标1：确定产前CD暴露对T调节细胞的影响；目标2：确定在胸腺细胞发育中CDTX新生后代作用中Wnt10b活性降低的作用；并且，目标3：确定CDTX后代由于AB产生增加而表现出加重自身免疫性诱导的病理的潜力。