The overall goal of this research is to test the hypothesis that there are differences in response to the immunotoxic effects of mercury compounds in humans, and that susceptibility determinants are enriched in families with cases of autism/autism spectrum disorders (ASD). This research is relevant to understanding preventable risk factors for autism/ASD, based upon the hypothesis that mercury compounds by themselves do not cause autism/ASD but may contribute to the risks of autism/ASD through their immunotoxic properties, in combination with genetic susceptibility and co-exposures to other risks, such as infections. Based upon extensive findings of genetically determined susceptibility to mercury immunotoxicity in rats and mice, we hypothesize that there is a range of susceptibility for mercury-induced immunotoxicity in human populations. We specifically hypothesize, based upon the experimental literature by us and others, that individuals within families with multiple cases of autism/ASD, will have heightened responsiveness to the immunotoxic effects of mercury compounds. The eventual goal of this research is to identify candidate genes that influence individual responsiveness to the immunotoxic effects of mercury compounds. In order to accomplish this goal there is a primary need to define the phenotype of mercury-induced immunotoxicity, which is the goal of this project. We will test in vitro responsiveness to mercury in PBMCs obtained from volunteers. Responses will be measured by FACS analysis of cell surface markers and by ELISA measurements of released cytokines. A dose-response curve will be carried out, in vitro, in order to determine the slope for each individual. Replicability will be assessed by repeat measures of the same individuals; method validation will be completed by analysis of a new set of individuals. The overall relevance of the in vitro system will first be tested by comparing PBMCs from men and women (cycling, in the luteal phase). In the second phase, we will test the hypothesis that patients with autism are more susceptible to mercury-induced immunotoxicity by comparing in vitro responses of PBMCs among family trios (autism cases plus parents) with unrelated controls. Accomplishing the goals of this project will be the first stage in developing a broader study of gene-environment interactions in autism, as well as a targeted search for candidate genes related to mercury susceptibility in humans. ? ? ?
| Gardner, Renee M; Nyland, Jennifer F; Silbergeld, Ellen K (2010) Differential immunotoxic effects of inorganic and organic mercury species in vitro. Toxicol Lett 198:182-90 |
| Gardner, Renee M; Nyland, Jennifer F; Silva, Ines A et al. (2010) Mercury exposure, serum antinuclear/antinucleolar antibodies, and serum cytokine levels in mining populations in Amazonian Brazil: a cross-sectional study. Environ Res 110:345-54 |
| Gardner, Renee M; Nyland, Jennifer F; Evans, Sean L et al. (2009) Mercury induces an unopposed inflammatory response in human peripheral blood mononuclear cells in vitro. Environ Health Perspect 117:1932-8 |
