Developmental immunotoxicity induced by prenatal cadmium exposure

描述（由申请人提供）：镉是一种重金属和致癌物，存在于超级基金场所、电池制造设施、锌冶炼厂内部和周围以及香烟（最常见的暴露途径）中。一项对镉污染严重地区5至14岁儿童的流行病学研究表明，镉暴露与免疫调节之间存在高度相关性1。虽然这些儿童的母亲可能携带沉重的镉身体负担在怀孕期间的孩子，产前暴露（而不是出生后暴露）对测量免疫调节的直接影响不能被忽视，一个重要的考虑因素，因为出生后的影响产前和成人暴露于外源性物质往往显着不同。C57 Bl/6小鼠产前暴露于镉导致调节性T细胞（Treg）数量减少，并显着增加抗体（Ab）的雌性后代长达20周的年龄。Wnt水平也显着降低2，并且Wnt信号传导与Treg细胞的产生和稳定性有关。因此，我们将测试的假设，产前镉暴露减少Wnt信号，导致Treg细胞功能下降，随后，增加抗体的生产。有限的流行病学证据，再加上我们的实验室研究，使用小鼠，意味着产前镉暴露可能的免疫后果引起警惕。我们提出的这项研究将解决总体假设，产前暴露于镉降低调节性T细胞（Treg）功能，导致抗体（Ab）显着增加，这可能导致更高的倾向发展自身免疫性疾病或减少肿瘤监视。它包括三个目标：目标1：确定产前镉暴露对T调节细胞的影响;目的2：确定CdTx新生儿后代在胸腺细胞发育中Wnt 10 b活性降低的作用;目的3：确定CdTx后代由于抗体产生增加而表现出自身免疫诱导的病理恶化的可能性。

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.