Short-Term Transcriptomic Points of Departure Are Consistent with Chronic Points of Departure for Three Organophosphate Pesticides across Mouse and Fathead Minnow
New approach methods (NAMs) can reduce the need for chronic animal studies. Here, we apply benchmark dose (concentration) (BMD(C))–response modeling to transcriptomic changes in the liver of mice and in fathead minnow larvae after short-term exposures (7 days and 1 day, respectively) to several dose...
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Toxics |
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| Online Access: | https://www.mdpi.com/2305-6304/11/10/820 |
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| author | Rubia Martin Monique Hazemi Kevin Flynn Daniel Villeneuve Leah Wehmas |
| author_facet | Rubia Martin Monique Hazemi Kevin Flynn Daniel Villeneuve Leah Wehmas |
| author_sort | Rubia Martin |
| collection | DOAJ |
| description | New approach methods (NAMs) can reduce the need for chronic animal studies. Here, we apply benchmark dose (concentration) (BMD(C))–response modeling to transcriptomic changes in the liver of mice and in fathead minnow larvae after short-term exposures (7 days and 1 day, respectively) to several dose/concentrations of three organophosphate pesticides (OPPs): fenthion, methidathion, and parathion. The mouse liver transcriptional points of departure (TPODs) for fenthion, methidathion, and parathion were 0.009, 0.093, and 0.046 mg/Kg-bw/day, while the fathead minnow larva TPODs were 0.007, 0.115, and 0.046 mg/L, respectively. The TPODs were consistent across both species and reflected the relative potencies from traditional chronic toxicity studies with fenthion identified as the most potent. Moreover, the mouse liver TPODs were more sensitive than or within a 10-fold difference from the chronic apical points of departure (APODs) for mammals, while the fathead minnow larva TPODs were within an 18-fold difference from the chronic APODs for fish species. Short-term exposure to OPPs significantly impacted acetylcholinesterase mRNA abundance (FDR <i>p</i>-value <0.05, |fold change| ≥2) and canonical pathways (IPA, <i>p</i>-value <0.05) associated with organism death and neurological/immune dysfunctions, indicating the conservation of key events related to OPP toxicity. Together, these results build confidence in using short-term, molecular-based assays for the characterization of chemical toxicity and risk, thereby reducing reliance on chronic animal studies. |
| first_indexed | 2024-03-10T20:51:20Z |
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| language | English |
| last_indexed | 2024-03-10T20:51:20Z |
| publishDate | 2023-09-01 |
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| series | Toxics |
| spelling | doaj.art-e9243192a8504b6c8d6274be239ebce22023-11-19T18:21:28ZengMDPI AGToxics2305-63042023-09-01111082010.3390/toxics11100820Short-Term Transcriptomic Points of Departure Are Consistent with Chronic Points of Departure for Three Organophosphate Pesticides across Mouse and Fathead MinnowRubia Martin0Monique Hazemi1Kevin Flynn2Daniel Villeneuve3Leah Wehmas4Office of Research and Development, Center for Computational Toxicology and Exposure, Chemical Characterization and Exposure Division, Oak Ridge Institute for Science and Education, U.S. Environmental Protection Agency, Durham, NC 27709, USAOffice of Research and Development, Center for Computational Toxicology and Exposure, Great Lakes Ecology Division, Oak Ridge Institute for Science and Education, U.S. Environmental Protection Agency, Duluth, MN 55804, USAOffice of Research and Development, Center for Computational Toxicology and Exposure, Great Lakes Ecology Division, U.S. Environmental Protection Agency, Duluth, MN 55804, USAOffice of Research and Development, Center for Computational Toxicology and Exposure, Great Lakes Ecology Division, U.S. Environmental Protection Agency, Duluth, MN 55804, USAOffice of Research and Development, Center for Computational Toxicology and Exposure, Chemical Characterization and Exposure Division, U.S. Environmental Protection Agency, Durham, NC 27709, USANew approach methods (NAMs) can reduce the need for chronic animal studies. Here, we apply benchmark dose (concentration) (BMD(C))–response modeling to transcriptomic changes in the liver of mice and in fathead minnow larvae after short-term exposures (7 days and 1 day, respectively) to several dose/concentrations of three organophosphate pesticides (OPPs): fenthion, methidathion, and parathion. The mouse liver transcriptional points of departure (TPODs) for fenthion, methidathion, and parathion were 0.009, 0.093, and 0.046 mg/Kg-bw/day, while the fathead minnow larva TPODs were 0.007, 0.115, and 0.046 mg/L, respectively. The TPODs were consistent across both species and reflected the relative potencies from traditional chronic toxicity studies with fenthion identified as the most potent. Moreover, the mouse liver TPODs were more sensitive than or within a 10-fold difference from the chronic apical points of departure (APODs) for mammals, while the fathead minnow larva TPODs were within an 18-fold difference from the chronic APODs for fish species. Short-term exposure to OPPs significantly impacted acetylcholinesterase mRNA abundance (FDR <i>p</i>-value <0.05, |fold change| ≥2) and canonical pathways (IPA, <i>p</i>-value <0.05) associated with organism death and neurological/immune dysfunctions, indicating the conservation of key events related to OPP toxicity. Together, these results build confidence in using short-term, molecular-based assays for the characterization of chemical toxicity and risk, thereby reducing reliance on chronic animal studies.https://www.mdpi.com/2305-6304/11/10/820benchmark dosefathead minnowmouseorganophosphate pesticidestranscriptional points of departure |
| spellingShingle | Rubia Martin Monique Hazemi Kevin Flynn Daniel Villeneuve Leah Wehmas Short-Term Transcriptomic Points of Departure Are Consistent with Chronic Points of Departure for Three Organophosphate Pesticides across Mouse and Fathead Minnow Toxics benchmark dose fathead minnow mouse organophosphate pesticides transcriptional points of departure |
| title | Short-Term Transcriptomic Points of Departure Are Consistent with Chronic Points of Departure for Three Organophosphate Pesticides across Mouse and Fathead Minnow |
| title_full | Short-Term Transcriptomic Points of Departure Are Consistent with Chronic Points of Departure for Three Organophosphate Pesticides across Mouse and Fathead Minnow |
| title_fullStr | Short-Term Transcriptomic Points of Departure Are Consistent with Chronic Points of Departure for Three Organophosphate Pesticides across Mouse and Fathead Minnow |
| title_full_unstemmed | Short-Term Transcriptomic Points of Departure Are Consistent with Chronic Points of Departure for Three Organophosphate Pesticides across Mouse and Fathead Minnow |
| title_short | Short-Term Transcriptomic Points of Departure Are Consistent with Chronic Points of Departure for Three Organophosphate Pesticides across Mouse and Fathead Minnow |
| title_sort | short term transcriptomic points of departure are consistent with chronic points of departure for three organophosphate pesticides across mouse and fathead minnow |
| topic | benchmark dose fathead minnow mouse organophosphate pesticides transcriptional points of departure |
| url | https://www.mdpi.com/2305-6304/11/10/820 |
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