# Investigating obesity-induced altered ovarian intracellular signaling

> **NIH NIH R01** · IOWA STATE UNIVERSITY · 2021 · $515,089

## Abstract

Project summary: Obesity is a global public health issue. A number of chemicals precipitate amenorrhea,
premature menopause and infertility in females. Affected women experience chronic, permanent health effects
since the proportion of their life spent post-menopause is lengthened, thereby increasing the likelihood of
associated health complication development (including coronary heart disease, obesity, type II diabetes,
osteoporosis and depression). Reproductive dysfunction also results from obesity and we have published a
number of studies demonstrating that the ovary of an obese female has heightened sensitivity to chemical
exposures that induce ovarian damage and infertility. This increased sensitivity arises from altered abundance
of chemical metabolism proteins within the ovary and raises concern about increased risk to obese women of
environmental chemical exposures that target the ovary.
 Our strong published and preliminary data support that the ovary of obese females have altered chemical
metabolism in addition to a blunted DNA repair response when exposed to chemicals that cause DNA damage.
This is concerning since DNA damage can lead to loss of fertility in females or represent a risk to offspring
health should this damage be improperly repaired. Indeed, offspring of obese women have increased rates of
birth defects. We have demonstrated our findings in adult post-pubertal mice, however, whether these impacts
are also noted in females who experience an obese environment during gestation or pre-pubertally remains
unclear but represents a major concern for female public health. In light of our strong and worrying evidence
for a heightened sensitivity of the obese female ovary to chemical-induced damage, we will mechanistically
investigate our central hypothesis that obesity potentiates ovotoxicity through reduced repair of DNA
damage, altered ovarian chemical biotransformation, and induction of oxidative stress. We will utilize
the alkylating agent, dimethylbenz[a]anthracene (DMBA) to induce ovarian DNA damage at three stages of
importance in ovarian development; during gestation, pre-puberty and post-puberty. We will investigate our
hypothesis through completion of three specific aims: Aim 1 will investigate obesity effects on DNA repair
response to DMBA exposure; Aim 2 will examine obesity-induced impacts on DMBA chemical metabolism; and
Aim 3 will determine effects of DMBA exposure and obesity on induction of ovarian oxidative stress. This work
is applicable to general female health, ovarian toxicity, infertility and even extends to carcinogenesis. The data
has basic and translational importance and is relevant to the NIEHS mission. This proposal is pioneering,
innovative, and couples the additive effect of altered physiological and metabolic status on ovarian toxicity that
occurs as a consequence of environmental chemical exposures.

## Key facts

- **NIH application ID:** 10077481
- **Project number:** 5R01ES030341-02
- **Recipient organization:** IOWA STATE UNIVERSITY
- **Principal Investigator:** Aileen Frances Keating
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $515,089
- **Award type:** 5
- **Project period:** 2020-01-01 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077481

## Citation

> US National Institutes of Health, RePORTER application 10077481, Investigating obesity-induced altered ovarian intracellular signaling (5R01ES030341-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10077481. Licensed CC0.

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