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Intergenerational Arsenic Exposure on the Mouse Epigenome and Metabolic Physiology
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  • Mathia Colwell,
  • Nicole Wanner,
  • Amanda Rezabek,
  • Christopher Faulk
Mathia Colwell
University of Michigan Michigan Medicine

Corresponding Author:[email protected]

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Nicole Wanner
University of Minnesota
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Amanda Rezabek
University of Minnesota Twin Cities
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Christopher Faulk
University of Minnesota
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Inorganic Arsenic (iAs) is one of the largest toxic exposures to impact humanity worldwide. Exposure to iAs during pregnancy may disrupt the proper remodeling of the epigenome of F1 developing offspring and potentially their F2 grand-offspring via disruption of fetal primordial germ cells (PGCs). There is a limited understanding between the correlation of disease phenotype and methylation profile within offspring of both generations and whether it persists to adulthood. Our study aims to understand the intergenerational effects of in utero iAs exposure on the epigenetic profile and onset of disease phenotypes within F1 and F2 adult offspring, despite the life-long absence of direct arsenic exposure within these generations. We exposed F0 female mice (C57BL6/J) to the following doses of iAs in drinking water 2 weeks before pregnancy until the birth of the F1 offspring: 1 ppb, 10 ppb, 245 ppb, and 2300 ppb. We found sex- and dose-specific changes in weight and body composition that persist from early time to adulthood within both generations. Fasting blood glucose challenge suggests iAs exposure causes dysregulation of glucose metabolism, revealing generational, exposure, and sex specific differences. Toward understanding the mechanism, genome-wide DNA methylation data highlights exposure-specific patterns in liver, finding dysregulation within genes associated with cancer, T2D, and obesity. We also identified regions containing persistently differentially methylated CpG sites between F1 and F2 generations. Our results indicate F1 developing embryos and F2 PGCs retain epigenetic damage established during the prenatal period and are associated with adult metabolic dysfunction.
07 Nov 2022Review(s) Completed, Editorial Evaluation Pending
07 Nov 2022Editorial Decision: Revise Minor
02 Dec 20221st Revision Received
05 Dec 2022Submission Checks Completed
05 Dec 2022Review(s) Completed, Editorial Evaluation Pending
05 Dec 2022Assigned to Editor
06 Dec 2022Reviewer(s) Assigned
26 Dec 2022Editorial Decision: Accept