Superfund Research Program
Systems Toxicology of Environmental Contaminants
Over the past year, Forest White, Ph.D., and his researh team have continued to explore the systems-level response to exposure to single-agent environmental contaminants. Specifically, the team has quantified the response to acute exposure to three concentrations of benzo[a]pyrene (BaP), an exemplar PAH, in lung and liver cancer cell lines at one, three, and six days of treatment. In both lung and liver cell lines project researchers have detected an initial increase in DNA damage response (DDR) that decreases over time, despite continued exposure to BaP. At the same time, project researchers detect a dose- and time-dependent increase in tyrosine phosphorylation (pTyr), including an enrichment of proteins associated with receptor tyrosine kinase signaling. Altered pTyr signaling also includes decreased phosphorylation of cell-cell junction proteins, indicative of increased migratory signaling. Accordingly, cells exposed to BaP demonstrate a significant increase in 2D migration by a scratch-wound assay. While a tenuous connection between exposure to PAHs and increased migration has been previously seen, here the team has uncovered some of the mechanistic signaling driving that response. The researchers have also quantified the systems-level response to exposure to NDMA in mouse livers in vivo, across wild-type,Aag-/-, AagTg (overexpressing Aag), and Mgmt-/- mice, in collaboration with the Assessment of Genotoxic Health Risks at Superfund Sites through Mutational Signatures and NDMA and DNA Alkylation Repair in the Liver Projects. AagTg mice have increased DDR signaling even in the absence of treatment, while exposure to NDMA drives an increase in DDR signaling in all genotypes. Intriguingly, NDMA exposure leads to a massive increase in pTyr signaling, with AagTg and Mgmt-/- mice demonstrating the largest response. Increased pTyr signaling persists for at least 10 weeks and includes inflammatory and oncogenic signaling cascades.