The Nerve Terminal as the Site of Action for Type-2 Alkenes

DESCRIPTION (provided by applicant): This is a ViCTER-based revision of a parent R01 research program (ES003830-25-28) which was designed to determine whether exposure to a mixture of type-2 alkenes can cause toxicity or accelerate endogenous disease processes. The type-2 alkenes are a large family of well-known electrophilic environmental toxicants that produce toxicity via a common mechanism. The principal investigators have hypothesized that, although the environmental concentration of an individual type-2 alkene might not be toxic, chronic low-level exposure to a mixture of these chemicals might be toxicologically relevant. Although the parent R01 research will provide important information, a comprehensive understanding of type-2 alkene toxicity is dependent upon more definitive mechanistic studies at the chemical and molecular levels. Specifically, there is exciting new evidence that selenium (Se)-containing proteins are additional nucleophilic targets for electrophiles and that these targets have substantial toxicological significance. Therefore, in this revised R01 ViCTER program Dr. Richard M. LoPachin (original R01 principal investigator) and Dr. Terrence Gavin (collaborator) will conduct research to determine whether selenocysteine (Sec)-directed enzymes are toxicologically subject to attack by environmental type-2 alkenes and other soft electrophiles. To explore possible Se-based mitigation strategies, Dr. Nicholas V.C. Ralston (ViCTER collaborator) will determine the influence of Se-supplementation and administration of Se-containing compounds on type-2 alkene cytotoxicity. Despite the prevalence and toxicity of the type-2 alkenes, there is a complete lack of knowledge regarding the metrics of human environmental exposure. Accordingly, Dr. Pam Factor-Litvak (ViCTER collaborator) will direct a pilot, epidemiological study to assess the extent of type-2 alkene exposure and possible toxic consequences in a cohort of mothers and newborns. An important component of this research will be to examine the possible association between mother-baby Se plasma levels and toxicological outcomes. The common theme of this research is Se as a molecular target for mediating both toxicity (selenoenzymes) and cytoprotection (Se-containing compounds). The proposed research will dramatically expand the scope of the R01 program and, based on the assembly of scientists with diverse expertise, the ViCTER organization will take an interdisciplinary approach to the proposed research. The newly formed association represents a unique opportunity to move the parent research into the realm of human epidemiology and to expand their mechanistic understanding of type-2 alkene toxicity. The results could lead to a comprehensive understanding of the Se-based molecular aspects that govern the toxicity caused by soft electrophiles. Complementary studies defining the respective neuroprotective abilities of the selenocompounds could lead to the discovery of new pharmacotherapeutic approaches. Finally, results from the proposed epidemiological research could provide a rational basis for type-2 alkene risk assessment and the establishment of reliable exposure limits in human populations.