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 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.

The role of tumor necrosis factor alpha and the peroxisome proliferator-activated receptor alpha in modulating the effects of fumonisin in mouse liver.

Fumonisins are mycotoxins that are produced by Fusarium verticillioides found in corn and corn-based foods, and are suspected human esophageal carcinogens. Exposure of rodents to fumonisin B1 causes hepatotoxicity and results in alterations in the balance between cell proliferation and apoptosis in the liver. As the cytokine tumor necrosis factor alpha (TNFalpha) and the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) also modulate hepatocyte proliferation and apoptosis, we tested the hypothesis that fumonisin-induced hepatotoxicity in the liver is modulated by these factors. We examined the effects of dietary exposure to a fumonisin-containing culture material (CM) of the fungus F. verticillioides for 8 days or 5 weeks in the livers of mice lacking either TNFalpha or PPARalpha. Compared to wild-type mice TNFalpha-null mice exhibited increased hepatocyte proliferation and apoptosis. In contrast, PPARalpha-null and wild-type mice were found to exhibit similar patterns of hepatocyte apoptosis and proliferation when fed the CM diet. Overall, these findings provide evidence that TNFalpha, but not PPARalpha, plays a role in modulating fumonisin-induced hepatotoxicity in mice.