Superfund Research Program
Developmental Toxicity of non-Dioxin-like PCBs and Chemical Mixtures
Studies have confirmed preliminary data that expression of PXR is self-regulated in embryos. In parallel with the embryo studies, investigators examined PXR expression in adult organs, and found high levels of expression in eye, optic nerve and brain, not been reported in other species. By comparison, a target gene (CYP3A65), ostensibly under control of the PXR, was expressed principally in the liver and intestine, consistent with earlier data and other reports. Cloning and sequencing of the suspected PXR from the eye confirmed that it is indeed PXR. This suggests that there may be heretofore un-recognized functions of the PXR.
Researchers also have determined that there are variant forms (alleles) of the PXR in zebrafish. In studies done in collaboration with scientists in Norway and at UC Irvine (leveraging in-kind contribution to BU SRP studies), the PXR variants have been shown to have very different capacities for being "activated" by chemicals. This functional PXR variation means that different laboratory strains of this important model organism may respond quite differently to the many chemicals that act via this receptor.
Progress also was made in examining responses of killifish from New Bedford Harbor to ortho-PCBs, by analysis of ryanodine receptor (RyR) expression and function (in collaboration with scientists at the UC Davis SRP). These calcium channels are involved in regulating a number of physiological and pathophysiological processes in the central and peripheral nervous systems and musculature, and in mammals RyRs are targets for ortho-PCBs. The skeletal muscle isoform, RyR1, in NBH killifish displayed altered ligand binding and differential calcium sensitivity compared to fish from a reference population. NBH killifish also had elevated expression of genes that are known to play a role in PCB-mediated toxicity via the RyR. Further studies to understand these PCB induced alterations are underway.