In vitro transcriptomic analyses reveal pathway perturbations, estrogenic activities, and potencies of data-poor BPA alternative chemicals
- DOI
- Language of the publication
- English
- Date
- 2022-12-19
- Type
- Article
- Author(s)
- Matteo, Geronimo
- Leingartner, Karen
- Rowan-Carroll, Andrea
- Meier, Matthew
- Williams, Andrew
- Beal, Marc A.
- Gagné, Matthew
- Farmahin, Reza
- Wickramasuriya, Shamika
- Reardon, Anthony J.F.
- Barton-Maclaren, Tara
- Corton, Christopher J.
- Yauk, Carole L.
- Atlas, Ella
- Publisher
- Oxford University Press
Abstract
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 µM) for 48 h. TempO-Seq (BioSpyder Inc) was used to examine global transcriptomic changes and estrogen receptor alpha (ERα)-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. ERα activation was evaluated using a published transcriptomic biomarker and an ERα-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 ERα active. Global and ERα 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.
Plain language summary
Canada was the first country to take regulatory action on bisphenol A (BPA) in 2010 due to its hormone disrupting effects. Since then, industry has shifted towards chemically related alternatives in place of BPA. With increased use, several BPA replacement chemicals are now detected in humans and the environment worldwide. Unfortunately, many of these alternative chemicals are not well studied and their effects on human health are unknown. In the current study, Health Canada regulatory and research scientists collaborated to assess the toxicological potency and possible modes of action of alternative chemicals relative to the prototype chemical, BPA. Further, as BPA interacts with the human estrogen receptor (ER) to exert its deleterious effects, this research sought to evaluate the ability of alternative chemicals to interact with the ER. Human cells were exposed to BPA and several alternative chemicals and changes in gene expression across the whole genome were measured. The results showed that alternative chemicals that are structurally similar to BPA had the most similar potencies. Further, these alternatives and BPA affected gene expression in pathways associated with dysregulated cell growth and cancer. This research also identified several alternative chemicals that activate the ER, and that bisphenol AF was the most estrogenic chemical tested. These data support a growing body of evidence that suggest that BPA alternative chemicals can have deleterious effects at similar concentrations as BPA. Finally, this research will support risk assessment activities by Health Canada.
Subject
- Health,
- Health and safety