In vitro transcriptomic analyses reveal pathway perturbations, estrogenic activities, and potencies of data-poor BPA alternative chemicals

Since initial regulatory action in 2010 in Canada, bisphenol A (BPA) has been progressively replaced by structurally related alternative chemicals. Unfortunately, many of these chemicals are data-poor, limiting toxicological risk assessment. We used high-throughput transcriptomics to evaluate potential hazards and compare potencies of BPA and 15 BPA alternative chemicals in cultured breast cancer cells. MCF-7 cells were exposed to BPA and 15 alternative chemicals (0.0005-100 mu M) for 48 h. TempO-Seq (BioSpyder Inc) was used to examine global transcriptomic changes and estrogen receptor alpha (ER alpha)-associated transcriptional changes. Benchmark concentration (BMC) analysis was conducted to identify 2 global transcriptomic points of departure: (1) the lowest pathway median gene BMC and (2) the 25th lowest rank-ordered gene BMC. ER alpha activation was evaluated using a published transcriptomic biomarker and an ER alpha-specific transcriptomic point of departure was derived. Genes fitting BMC models were subjected to upstream regulator and canonical pathway analysis in Ingenuity Pathway Analysis. Biomarker analysis identified BPA and 8 alternative chemicals as ER alpha active. Global and ER alpha transcriptomic points of departure produced highly similar potency rankings with bisphenol AF as the most potent chemical tested, followed by BPA and bisphenol C. Further, BPA and transcriptionally active alternative chemicals enriched similar gene sets associated with increased cell division and cancer-related processes. These data provide support for future read-across applications of transcriptomic profiling for risk assessment of data-poor chemicals and suggest that several BPA alternative chemicals may cause hazards at similar concentrations to BPA.

Automated summary

Since 2010, BPA has been replaced by alternative chemicals in Canada. However, many of these chemicals lack sufficient data for toxicological risk assessment. In this study, high-throughput transcriptomics was used to assess the hazards of BPA and 15 alternative chemicals in breast cancer cells. The results indicate that several BPA alternative chemicals may cause similar hazards at similar concentrations to BPA, highlighting the importance of transcriptomic profiling for risk assessment of data-poor chemicals.