In vitro transcriptomic analyses reveal pathway perturbations, estrogenic activities, and potencies of data-poor BPA
Geronimo Matteo1,2, Karen Leingartner1,2, Andrea Rowan-Carroll1,2
1Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch (HECSB) Health Canada, Ottawa, Ontario K2K 0K9, Canada.
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.
Insights
Bisphenol A (BPA) alternatives were tested for potential hazards using high-throughput transcriptomics. Several BPA alternatives showed estrogen receptor activity and similar potency to BPA, raising concerns for human health.
Area of Science:
- Toxicology
- Genomics
- Endocrinology
Background:
- Bisphenol A (BPA) has been replaced by alternative chemicals since 2010.
- Many BPA alternatives lack toxicological data, hindering risk assessment.
Purpose of the Study:
- To evaluate potential hazards and compare potencies of BPA and 15 alternatives.
- To assess estrogen receptor alpha (ERα) activity and associated transcriptional changes.
Main Methods:
- High-throughput transcriptomics (TempO-Seq) on MCF-7 breast cancer cells.
- Benchmark concentration (BMC) analysis for global and ERα-specific transcriptomic points of departure.
- Ingenuity Pathway Analysis for upstream regulator and canonical pathway analysis.
Main Results:
- BPA and 8 alternatives were identified as ERα active.
- Potency rankings were similar for global and ERα transcriptomic data, with bisphenol AF, BPA, and bisphenol C being most potent.
- Transcriptional changes indicated enrichment of cell division and cancer-related processes.
Conclusions:
- Transcriptomic profiling supports read-across for data-poor chemical risk assessment.
- Several BPA alternatives may pose hazards at concentrations similar to BPA.
