抄録
The effects of exposure to a mixture of brominated flame retardants (BFRs, primarily polybrominated diphenyl ethers, PBDEs) on ovarian function and gene expression have been studied in an animal model, the human KGN granulosa cell line, and primary human mural and cumulus granulosa cells. Dietary exposure of female rats to the BFR mixture found in house dust prior to and during pregnancy had adverse effects on ovarian folliculogenesis and steroidogenesis in the dam; these effects were not accompanied by changes in the expression of a number of genes involved in these processes in the ovary, with the exception of Cyp17a1. Interestingly, female offspring exposed to this BFR mixture in utero and during lactation displayed accelerated puberty and disrupted folliculogenesis that were accompanied by treatment group-specific effects on the expression of ovarian genes in the estradiol, PPAR, CREB1 and EGF pathways. Since granulosa cells regulate steroidogenesis and communicate with the oocyte during follicular development, we examined the effects of exposure to the BFR mixture found in human follicular fluid on gene expression in KGN cells. Transcriptomic analyses revealed changes in the expression of genes related to reactive oxygen species (ROS), steroidogenesis and inflammatory response signalling. We then determined whether PBDE exposures were associated with effects on global gene expression in human cumulus and mural granulosa cells obtained from women undergoing an IVF procedure. Principal component analysis revealed extensive differences in gene expression between these two cell types. Interestingly, pathways were identified that were enriched in both mural and cumulus granulosa cells and were differentially regulated in association with high or low quartile exposure to specific PBDE congeners. Thus, there were striking differences in gene expression in association with both cell type and PBDE exposures. The affected pathways included those involved in nuclear receptor signalling and cell-cycle progression. In mural granulosa cells, pathways involved in immune function and signalling were predicted to be activated in association with high PBDE exposure. Together, these data reveal that gene expression signatures are highly cell-type specific and that even closely related congeners may be associated with a distinctive response. Supported by CIHR.
