# Intergenerational Arsenic Exposure on Mouse Epigenetics

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2022 · $12,853

## Abstract

PROJECT SUMMARY: Inorganic Arsenic (iAs) is one of the largest toxic exposures to impact humanity
worldwide, with over 140 million people exposed to iAs via contaminated drinking water. Exposure to iAs
during pregnancy disrupts normal DNA methylation patterns in developing offspring and leads to the onset of
adult diseases such as type II diabetes (T2D), cardiovascular disease, and cancers. More specifically,
disruption during pregnancy attenuates the proper remodeling of the epigenome of the F1 developing offspring
and potentially its F2 grand-offspring via disruption of fetal primordial germ cells (PGCs). However, there is a
limited understanding between the correlation between the disease phenotype and methylation profile within
the F1 offspring. Furthermore, we do not know whether iAs exposure alters epigenetic remodeling in F2 grand-
offspring and if the F2 generation is also at risk for developing iAs associated diseases even without direct iAs
exposure. Mechanistically, epigenetic reprogramming could be disrupted within the primordial germ cells,
resulting in differential DNA methylation and detrimental metabolic health in F2 offspring. The mechanism is as
follows: iAs is metabolized enzymatically by methylation, using S-adenosylmethionine (SAM) as a methyl
group donor. SAM is also normally used in DNA methylation to maintain the epigenome via the enzymatic
addition of a methyl group to unmodified cytosines. Thus, the competition of SAM for both methylation
pathways results in methyl group deficiency leading to less iAs conversion (increased toxicity) and less DNA
methylation (mis-regulation of gene expression). The central hypothesis is that intergenerational effects of in
utero iAs exposure will impact 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. Aim 1 will establish
the effects of iAs on F1 epigenetic remodeling during embryogenesis, focusing on genes associated with
development of obesity and T2D during adulthood. To confirm the maternal effect of iAs exposure on
epigenetic remodeling, the validated Agouti Avy mouse model epigenetic biosensor will be used to indicate loss
or gain of DNA methylation by shifting coat color. Aim 2 will characterize the F2 (adult grand-offspring) effects
of arsenic exposure on epigenetic remodeling in F1 primordial germ cells. For both aims, global DNA
methylation and hydroxymethylation will be quantified in somatic and germ tissues by liquid chromatography
mass-spectrometry and site specific methylation by pyrosequencing. Glucose tolerance and body composition
will be measured in adult F1 and F2 offspring as indications of disease present in adulthood. Collectively, these
experiments will provide a better understanding of the effects of iAs heavy metal exposure on intergenerational
epigenetics, the onset of adult disease in subsequent generations, and targets of multigenerational ...

## Key facts

- **NIH application ID:** 10217041
- **Project number:** 5F31ES030967-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Mathia Loren Colwell
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $12,853
- **Award type:** 5
- **Project period:** 2020-12-01 → 2022-03-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217041

## Citation

> US National Institutes of Health, RePORTER application 10217041, Intergenerational Arsenic Exposure on Mouse Epigenetics (5F31ES030967-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10217041. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*