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.
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) and this application requests funds to study the mechanism of cadmium-induced immunotoxicity after prenatal exposure. Prenatal exposure to Cd in mice results in decreased regulatory T cells as well as increased antibody responses. In addition to understanding the mechanism of these effects, this application will determine if this portends females to developing autoimmune disease.