Superfund Research Program
Developmental Toxicity of non-Dioxin-like PCBs and Chemical Mixtures
This project continues to expand researchers’ understanding of PCB effects, and the molecular mechanisms possibly involved in the effects of ortho-PCBs on early vertebrate development, using zebrafish and killifish models. It is revealing possible novel mechanisms of ortho-PCB effects, and establishing the nature of PXR involvement. Elucidating interactions of ligands with receptor proteins may lead to interventions in toxic effects.
The research team has determined that PCB153 is not a strong ligand of zebrafish PXR, by comparing the zebrafish embryonic PCB153 transcriptome with that of RNA-seq data from fish exposed to pregnenolone, an authentic PXR ligand. However, other ortho-PCBs, notably PCB52 but not PCB95, do appear to induce transcriptional changes similar to pregnenolone. Previously research found that PCB153 and PCB52 dose-dependently increased CYP20A1 induction, and affected zebrafish behavior. Newly generated CYP20A1-knockout strains of zebrafish exhibit behavioral anomalies as larvae, including hypoactivity. PCB effects are being tested in this new strain. The research team has also generated multiple lines of PXR-null zebrafish, which are currently being tested for transcriptional responses to known and putative PXR ligands, including PCBs. The research team has determined that killifish from the population in New Bedford Harbor, which acquired resistance to toxicity of dioxin-like PCBs, are also resistant to the transcriptional effects of ortho-PCB153. Few genes exhibited altered brain transcription in response to either PCB153 or PCB126 in New Bedford fish, relative to control fish. Importantly, there were also very large sex differences in the responses to the different PCBs, pointing to the importance of considering sex as a variable in toxicological responses.