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，存在于超级基金场地，电池制造设施，锌冶炼厂内部及其周围以及香烟（最常见的接触途径）中。一项针对Cd严重污染地区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高度相关性。尽管这些儿童的母亲在其孩子怀孕期间可能携带着沉重的Cd身体负担，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-这是一个重要的考虑因素，因为产前和成人暴露于外源性药物的产后影响通常有显着差异。C57Bl/6小鼠产前暴露于Cd会导致雌性后代的调节性T细胞（Treg）数量减少，抗体（Ab）显著增加，直至20周龄。Wnt水平也显著降低2，Wnt信号传导与Treg细胞的产生和稳定性有关。因此，我们将验证产前Cd暴露降低Wnt信号导致Treg细胞功能下降并随后增加Ab产生的假设。有限的流行病学证据，加上我们使用小鼠进行的实验室研究，表明产前Cd暴露可能造成的免疫后果值得警惕。我们提出的这项研究将解决一个总体假设，即产前暴露于Cd会降低调节性T细胞（Treg）功能，导致抗体（Ab）显著增加，这可能导致发生自身免疫性疾病的更高倾向或降低肿瘤监测。它包括三个目标：目标1：确定产前Cd暴露对T调节细胞的影响；目的2：确定CdTx新生儿Wnt10b活性降低在胸腺细胞发育中的作用；目的3：确定CdTx后代由于Ab产生增加而表现出自身免疫诱导病理加剧的可能性。

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.