# Inter- and transgenerational effects of paternal arsenic exposure

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $472,448

## Abstract

ABSTRACT/SUMMARY
Industrialization had created widespread pollution, which has been steadily declining in developed countries for
decades. It is unclear whether and how long-lasting effects of environmental exposure persist across generations
and contribute to chronic diseases in later life. Inorganic arsenic (iAs) is the top chemical on the ATSDR priority
list of hazardous substances. Here we use iAs as a prototype environmental chemical to dissect the epigenetic
inheritance mechanisms in animal models. We focus exclusively on male-lineage exposure to avoid
developmental confounding effects due to in utero exposure. We found that the exposure of male mice to iAs in
drinking water caused glucose intolerance and upregulated hepatic glucose production in F1 females but not in
F1 male offspring. In contrast, paternal iAs decreased liver triglyceride content and circulating free fatty acids
levels in F1 males, but not F1 females. F0 sperm and F1 livers display altered DNA methylation and expression
in genes related to gonadal hormone signaling and lipid metabolism. In the F2 generation from the male-lineage
iAs exposure, mice display reduced adiposity, nutrient malabsorption, and the altered gut microbiome. We
hypothesize that the interplay between estrogen receptor, DNA methylation, non-coding RNAs, and gut
microbiome accounts for the inter- and transgenerational effects of iAs in metabolic physiology. We will
characterize how paternal iAs exposure alters glucose metabolism in F1 female offspring; address how paternal
iAs exposure alters lipid metabolism in F1 male offspring, and explore how paternal iAs exposure affects nutrient
absorption through altering the gut microbiome in F2 offspring. The mechanistic insights from this study will
advance our understanding of the cross-generational effects of environmental exposure on metabolic physiology
through the disruption of the endocrine system.

## Key facts

- **NIH application ID:** 10781975
- **Project number:** 5R01ES034768-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Zheng Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $472,448
- **Award type:** 5
- **Project period:** 2023-02-08 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10781975

## Citation

> US National Institutes of Health, RePORTER application 10781975, Inter- and transgenerational effects of paternal arsenic exposure (5R01ES034768-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10781975. Licensed CC0.

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