Superfund Research Program
Developmental Toxicity of non-Dioxin-like PCBs and Chemical Mixtures
There was substantial progress in addressing questions about how polychlorinated biphenyls (PCBs) especially ortho-PCBs, affect the health of fish, as revealed in molecular and other changes. John Stegeman, Ph.D., and his research team used both zebrafish (a research model) and killifish (highly exposed to PCBs in New Bedford Harbor). Results are reflected in publications (Bainy, 2013; Fritsch, 2015; Grans, 2015; Kubota, 2013; Lille-Langoy, 2015; Stegeman, 2015; Wincent, 2015). Stegeman and his team hypothesized that ortho-PCBs would elicit distinct molecular and phenotypic responses, and found that behavioral effects, especially hyperactivity, occurred in zebrafish larvae exposed to ortho-PCBs, without overt physical phenotypes.
In the past year the research team performed transcriptome analysis of embryos exposed to ortho-PCB153 for different periods, seeking acute (6 hr) and extended (24 hr) responses. Large numbers of genes were downregulated, more than 900 genes at 6 hr, and ca. 175 genes at 24 hr. Fewer genes were upregulated. Dysregulated genes included hypoxia response genes, genes involved in carbohydrate metabolism, and genes implicated in neurological dysfunction. PCB153 dose-dependently increased expression of an "orphan" cytochrome P450 gene CYP20A1 in embryos; more recently, methyl-mercury was found to down regulate this gene. Morpholino knock down of CYP20A1 caused increased activity consistent with hyperactivity, and decreased visual responsiveness in zebrafish larvae, suggesting a CYP20A1 role in behavioral effects of chemicals. The research team examined responses of killifish from New Bedford Harbor to ortho-PCBs, by analysis of ryanodine receptor (RyR) expression and function (in collaboration with the UC Davis SRP), and analysis of possible PXR regulated genes. The results suggest that the New Bedford killifish have an adaptation to the high levels of ortho-PCBs there.