The developing organism is in many ways highly sensitive to exogenous influences on development. For these reasons, there is a priority to identify developmental toxicants and especially to understand their mechanisms of action since this can assist us in developing science-based methods of hazard identification and prioritization. The least well understood class of developmental toxicants are agents that can affect the development of offspring consequent to preconception exposure of one or both parents, especially the male. Relatively few agents that may affect offspring development consequent to preconception paternal exposures have been identified, as compared to the number of agents identified as developmental toxicants associated with in utero exposures via the mother. Research in this area has been hampered by a lack of mechanistic understanding as to how preconception exposures of the male could affect the development of offspring during embryogenesis and into post-natal life. Recent advances in fundamental biology of development now make it appropriate to propose and test new hypotheses on the interaction of acquired risks with the molecular developmental program. Of particular relevance to this proposal is the new understanding of the importance of paternal or maternal-specific contributions to the genome of the zygote and the phenotype of the offspring. The overall goal of this project is to investigate the role of genomic imprinting as a mechanism of developmental neurotoxicity, associated with preconception exposure of paternal germ cells. The objectives are as follows: 1. To apply molecular methods to study parental specific allelic expression of imprinted genes in the zygote, following paternal preconception exposures to a model developmental neurotixicant. 2. To utilize high throughput methods to examine patterns of DNA methylation in candidate genes in sperm and zygote in order to detect the presence of male-mediated effects on imprinted genes involved in early development.
|Navas-Acien, Ana; Silbergeld, Ellen K; Sharrett, Richey et al. (2005) Metals in urine and peripheral arterial disease. Environ Health Perspect 113:164-9|