# Sex-Specific Metabolic and Epigenetic Programming of Cardiac Differentiation by Developmental Lead Exposure.

> **NIH NIH K01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $155,875

## Abstract

Abstract:
Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality world-wide, and there are
significant sex differences in their incidence, pathophysiology, and prognosis. Accumulating evidence suggests
an important role for early-life toxicant exposures in the etiology of CVDs; however, the molecular mechanisms
underlying these associations are unclear. In particular, the role for sex as a determinant of susceptibility to
toxicant-induced cardiovascular health effects remains poorly understood. Pb exposure continues to pose a
significant public health concern, particularly in poor urban areas. Perinatal and adult exposure to Pb are
associated with adverse cardiovascular effects in human and animal models. One important mechanism by
which early Pb exposure may influence the long-term risk of CVDs is through disruption of the precise
epigenetic programs governing normal cardiac development. Recent studies in cancer and stem cell biology
demonstrate that epigenetic changes and cellular differentiation are closely coupled to the metabolic state of
the cell, enabling cells to detect, and rapidly respond to, environmental cues. Notably, stem cells from male
and female donors exhibit intrinsic differences in differentiation programs, as well as differential sensitivity to
toxicant exposures. Despite known impacts of Pb exposure on heart function, the effects of developmental Pb
exposure on epigenetic and metabolic programming during cardiac development, and potential sex differences
in these effects, have not been investigated. Using an established mouse model of perinatal environmental
exposures, we have recently discovered that developmental Pb exposure leads to sex-specific changes in
DNA methylation in the hearts of adult offspring mice. We have further discovered that hearts of Pb-exposed
mice exhibit a significant increase in the oxidation of glutathione, a cellular antioxidant and metabolite that is
closely coupled to epigenetic programming and stem cell differentiation. These results suggest that perinatal
Pb exposure may disrupt normal metabolic and epigenetic programming in the heart in a sex-specific manner.
Using human patient-derived induced pluriopotent stem cells (iPSCs) from male and female donors, the goal of
this proposal is to elucidate the precise molecular mechanisms underlying Pb-induced programming on human
cardiac differentiation and function, and to understand how sex differences may influence susceptibility to this
toxicant. Preliminary studies in human iPSC-derived cardiomyocytes demonstrate that acute Pb exposure
promotes a dose-dependent increase in action potential duration, suggesting that Pb may have
arrhythmogenic effects, and demonstrating the utility of this model to assess Pb-induced effects on cardiac
function. The training and research outlined in this K01 proposal will provide an outstanding framework for the
development of a successful R01 application and an impactful career as an independent ...

## Key facts

- **NIH application ID:** 10246462
- **Project number:** 5K01ES032048-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Laurie Kathleen Svoboda
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $155,875
- **Award type:** 5
- **Project period:** 2020-08-25 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246462

## Citation

> US National Institutes of Health, RePORTER application 10246462, Sex-Specific Metabolic and Epigenetic Programming of Cardiac Differentiation by Developmental Lead Exposure. (5K01ES032048-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10246462. Licensed CC0.

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