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Short-Term Transcriptomic Points-of-Departure are Consistent with Chronic Points-of-Departure for Three Organophosphate Pesticides in Rodents
Citation:
Martin, R., S. Hester, AND L. Wehmas. Short-Term Transcriptomic Points-of-Departure are Consistent with Chronic Points-of-Departure for Three Organophosphate Pesticides in Rodents. ASCCT, Chapel Hill, NC, October 19 - 21, 2022. https://doi.org/10.23645/epacomptox.21824532
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Description:
Interest in the use of new approach methods could reduce the need for chronic-animal-based toxicity and carcinogenicity bioassays. Here, we employ a short-term dietary study in mice to quantify the transcriptomics points of departure (TPODs) of three previously studied organophosphate pesticides (OPP). We used targeted, whole transcriptome RNA-sequencing to evaluate expression changes in the liver of male mice after 7-days of dietary exposure to 4-dose-levels of fenthion, methidathion, or parathion. While OPPs are known to act through acetylcholinesterase (AChE) inhibition, we speculated that the liver, a major metabolic nexus of toxicant insult, might serve as a valid surrogate for measuring OPP PODs at the transcriptomic level. We modeled transcriptomic response using BMDExpress to identify the benchmark doses and TPODs for comparison to traditional, apical PODs. The TPOD for fenthion, parathion, and methidathion were 0.0124, 0.298, and 0.5673 mg/kg/day, which were within ±3-fold of the apical PODs based on AChE inhibition in the blood from two-year, chronic, dietary rodent studies. Furthermore, the significantly enriched gene sets defining the TPODs involved pathways and regulators of oxygen species induction, which are known to be impacted by OPPs. These results demonstrate that the liver transcriptome from a 7-day exposure could serve as a surrogate for evaluating global adverse effects indicative of chronic PODs. While additional research is needed, these results build confidence in using short-term molecular-based in vivo assays for the characterization of toxicity, thereby, reducing reliance on 2-year animal studies for chronic toxicity and carcinogenicity studies. This abstract does not reflect EPA policy.
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DOI: Short-Term Transcriptomic Points-of-Departure are Consistent with Chronic Points-of-Departure for Three Organophosphate Pesticides in Rodents
20221017_ORAL TALK NCSOT FINAL.PDF (PDF, NA pp, 824.759 KB, about PDF)