Genomic comparisons between hepatocarcinogenic and non-hepatocarcinogenic organophosphate insecticides in the mouse liver.

Autor: Rooney J; Oak Ridge Institute for Science and Education (ORISE) Research Participant at US EPA, Office of Research and Development, Center for Computational Toxicology and Exposure (formerly NHEERL), Research Triangle Park, NC, 27711, United States; National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States(3). Electronic address: jrooney@ils-inc.com., Wehmas LC; Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: wehmas.leah@epa.gov., Ryan N; Oak Ridge Institute for Science and Education (ORISE) Research Participant at US EPA, Office of Research and Development, Center for Computational Toxicology and Exposure (formerly NHEERL), Research Triangle Park, NC, 27711, United States; National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States(3). Electronic address: nataliaryan801@gmail.com., Chorley BN; Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: chorley.brian@epa.gov., Hester SD; Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: hester.susan@epa.gov., Kenyon EM; Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: kenyon.elaina@epa.gov., Schmid JE; National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States(3). Electronic address: jeschmid@mebtel.net., George BJ; Center for Public Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: george.bj@epa.gov., Hughes MF; Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: hughes.michaelf@epa.gov., Sey YM; Center for Public Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: sey.yusupha@epa.gov., Tennant AH; Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: tennant.alan@epa.gov., Simmons JE; Center for Public Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: Simmons.Jane@epa.gov., Wood CE; National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States(3). Electronic address: charleswood99@gmail.com., Corton JC; Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: corton.chris@epa.gov.
Jazyk: angličtina
Zdroj: Toxicology [Toxicology] 2022 Jan 15; Vol. 465, pp. 153046. Date of Electronic Publication: 2021 Nov 20.
DOI: 10.1016/j.tox.2021.153046
Abstrakt: Short-term biomarkers of toxicity have an increasingly important role in the screening and prioritization of new chemicals. In this study, we examined early indicators of liver toxicity for three reference organophosphate (OP) chemicals, which are among the most widely used insecticides in the world. The OP methidathion was previously shown to increase the incidence of liver toxicity, including hepatocellular tumors, in male mice. To provide insights into the adverse outcome pathway (AOP) that underlies these tumors, effects of methidathion in the male mouse liver were examined after 7 and 28 day exposures and compared to those of two other OPs that either do not increase (fenthion) or possibly suppress liver cancer (parathion) in mice. None of the chemicals caused increases in liver weight/body weight or histopathological changes in the liver. Parathion decreased liver cell proliferation after 7 and 28 days while the other chemicals had no effects. There was no evidence for hepatotoxicity in any of the treatment groups. Full-genome microarray analysis of the livers from the 7 and 28 day treatments demonstrated that methidathion and fenthion regulated a large number of overlapping genes, while parathion regulated a unique set of genes. Examination of cytochrome P450 enzyme activities and use of predictive gene expression biomarkers found no consistent evidence for activation of AhR, CAR, PXR, or PPARα. Parathion suppressed the male-specific gene expression pattern through STAT5b, similar to genetic and dietary conditions that decrease liver tumor incidence in mice. Overall, these findings indicate that methidathion causes liver cancer by a mechanism that does not involve common mechanisms of liver cancer induction.
(Published by Elsevier B.V.)
Databáze: MEDLINE
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