Developmental immunotoxicity induced by prenatal cadmium exposure

描述(申请人提供)：镉是一种重金属和致癌物质，存在于超级基金地点、电池制造设施、锌冶炼厂及其周围以及香烟中(最常见的暴露途径)。一项对Cd污染严重地区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高度相关1。虽然这些儿童的母亲在怀孕期间可能背负着沉重的镉身体负担，但无法区分产前暴露(而不是出生后暴露)对所测量的免疫调节的直接影响--这是一个重要的考虑因素，因为产前和成人暴露于外来物质的出生后影响往往截然不同。C57BL/6小鼠出生前暴露于镉可导致20周龄以下雌性后代调节性T细胞(Treg)数量减少，抗体(Ab)显著增加。WNT水平也明显降低2，WNT信号与Treg细胞的产生和稳定性有关。因此，我们将检验这一假设，即产前镉暴露降低了Wnt信号，从而导致Treg细胞功能下降，并随后增加了抗体的产生。有限的流行病学证据，再加上我们用小鼠进行的实验室研究，表明产前接触Cd可能产生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)显着增加，从而可能导致发生自身免疫性疾病的更高倾向或肿瘤监视减少。它包括三个目的：目的1：确定产前Cd暴露对T调节细胞的影响；目的2：确定Cd新生后代中Wnt10b活性降低在胸腺细胞发育中的作用；以及目标3：确定由于抗体产生增加而加剧自身免疫诱导的病理改变的可能性。

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.