Furan is a naturally forming compound found in heat-processed foods such as coffee, canned meats, and jarred baby food. It is concurrently found with analogues including 2-methylfuran (2-MF) and 3-methylfuran (3-MF), and toxicity studies demonstrate all are potent liver toxins. Toxicity studies found 3-MF is more toxic than either furan, or 2-MF. The present analysis assesses the transcriptional response in liver samples taken from male Fischer (F344) rats exposed to furan or 3-MF from 0 to 2.0 and 0-1.0 mg/kg bw/day, respectively, for 90 days. Transcriptional analyses found decreased liver function and fatty acid metabolism are common responses to both furan and 3-MF exposure. Furan liver injury promotes a ductular reaction through Hippo and TGFB signalling, which combined with increased immune response results in ameliorating perturbed bile acid homeostasis in treated rats. Failure to activate these pathways in 3-MF exposed rats and decreased p53 activity leads to cholestasis, and increased toxicity. Finally, BMD analysis indicate many of the most sensitive pathways affected by furan and 3-MF exposure relate to metabolism - malate dehydrogenase and glucose metabolism with BMDLs of 0.03 and 0.01 mg/kg bw/day for furan and 3-MF exposure, respectively, which agrees with BMDLs previously reported for apical and microarray data.

Ochratoxin A (OTA) is a mycotoxin produced by species of Penicillium and Aspergillus, and is found in many commodities including cereal grains, nuts, and coffee. OTA is a renal carcinogen and nephrotoxin at high concentrations, targeting the proximal tubules. This study uses transcriptomics and the previously reported apical data (Bondy et al., 2021) to infer mode-of-action of OTA toxicity in male and female rats exposed to low doses of OTA in utero and throughout development. Our findings support a male-specific activation of the innate and adaptive immune responses in F1 pups to OTA exposure. This was not found in the female F1 pups, and may be due to female-specific increased p38 activity and VDR signaling. Differentially expressed genes related to karyomegaly, MAPK activity, and immune activation appears to develop from in utero exposure to OTA whereas those related to decreased kidney and liver function, and changes to reproductive pathways occur in both rat generations. Together, these transcriptional results confirm that dietary exposure to OTA causes renal toxicity as well as alterations to hepatic and reproductive pathways in rats. In utero exposure of rats to OTA results in sex-specific alterations in immune response pathways, VDR signaling, and p38 activity.