# Phthalate Exposure and Female Reproductive Aging

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2023 · $543,353

## Abstract

The female reproductive system ages before any other physiological system, making it the most sensitive
indicator of aging. Most women experience reproductive senescence around age 51, but many women
experience early reproductive aging (early menopause). This is a serious public health problem because early
reproductive aging is associated with early onset of infertility and increased risk of several diseases and early
death. Further, the consequences of early reproductive senescence are significant in women who delay
childbirth for personal and professional reasons. Despite the profound impact of early reproductive aging on
women’s health, little is known about the mechanisms underlying early reproductive aging. Our published and
preliminary data indicate that acute exposure to the environmental chemicals, di-(2-ethyhexyl) phthalate (DEHP)
and diisononyl phthalate (DiNP), during adulthood increases several key indicators of early reproductive aging
in female mice. Further, published data indicate that activation of the inflammasome and inflammation are
hallmarks of reproductive aging and our preliminary data indicate that DEHP exposure increases inflammatory
macrophages in the hypothalamus, DEHP and DiNP exposure increase expression of inflammatory pathways in
the ovary, and DEHP activates resident macrophages in the peritoneal cavity. In addition, published studies
indicate that the aryl hydrocarbon receptor (AhR) plays an important role in regulating reproductive aging and
our preliminary data indicate that DEHP and its metabolite (MEHP) induce expression of the known AhR targets
in the pituitary and the ovary and that a specific AhR antagonist rescues ovarian follicles from phthalate-induced
inhibition of follicle growth. These impacts of phthalate exposure are of concern because phthalates are one of
the top contaminants present in human tissues and they are present in a myriad of consumer products, personal
care products, pesticides, wood finishes, adhesives, solvents, lubricants, defoaming agents, and medical
devices. Given our preliminary data, the importance of reproductive aging for reproductive health, and the
ubiquitous exposure of humans to phthalates, we propose to use mice to test the hypothesis that environmentally
relevant doses of DEHP and DiNP interact with the AhR pathway to cause inflammation and facilitate early
reproductive aging. To test this hypothesis, we will complete the following specific aims:1) compare the effects
of acute versus chronic exposure to environmentally relevant doses of DEHP and DiNP on the onset and
characteristics of reproductive aging, 2) determine if environmentally relevant phthalate exposure causes
inflammation, leading to early reproductive aging, and 3) determine if phthalates work through the AhR pathway
to cause early reproductive aging. Collectively, the proposed studies will greatly improve our understanding of
the mechanisms by which phthalate exposure causes early female reproductive aging...

## Key facts

- **NIH application ID:** 10576477
- **Project number:** 1R01ES034112-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Jodi A. Flaws
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $543,353
- **Award type:** 1
- **Project period:** 2022-12-01 → 2027-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10576477

## Citation

> US National Institutes of Health, RePORTER application 10576477, Phthalate Exposure and Female Reproductive Aging (1R01ES034112-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10576477. Licensed CC0.

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