# The intersection of stress and environmental chemicals in germ cell reprogramming

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $287,031

## Abstract

PROJECT ABSTRACT
The goal of this proposal is to establish how exposures to ubiquitous plastics and prenatal stress interact to
confer epigenetic changes to developing germ cells, and how such changes lead to reproductive and metabolic
phenotypes in later life and potentially in subsequent generations. Numerous studies involving consumer and
agricultural chemicals demonstrate effects that appear in the progeny and even grandchildren of individuals
exposed in utero. Correspondence between period of susceptibility and epigenetic reprogramming suggest that
epigenetic changes to germ cells are involved. However, as the majority of studies utilize oral gavage for
dosing, the effects of the chemical and prenatal stress are difficult to resolve. Phthalates are the major
chemical in household dust and have been detected in 100% of pregnant women in California. Our preliminary
studies in mice find that prenatal exposures to two different phthalates during the period of germ cell epigenetic
programming leads in each case to decreased repression of retrotransposons and germ cell developmental
defects; evidence from our lab suggests that this occurs through disruption of the piRNA pathway, which
silences endogenous transposable elements through epigenetic and post-translational mechanisms. In this
proposal, we will interrogate the combined and separate effects of biologically relevant doses of phthalate and
early gestational stress on the epigenetic state of mouse germ cells and relate these changes to the extent of
retrotransposon activity and reproductive phenotypes in the progeny. Studies in Aim 1 will determine how early
gestational stress and phthalate exposure interact to alter the epigenetic state of fetal germ cells and the
potential for inheritance of that state. This will disentangle the effects of stress and chemical exposure that
accompany oral gavage in many prior studies with quantifiable, molecular readouts as well as testing potential
mechanisms of direct and multigenerational epigenetic dysregulation. Aim 2 will examine phenotypic
consequences of early gestational stress and phthalate exposure on germ cells and female reproductive aging
in the next generation. By connecting adult reproductive phenotypes to fetal exposures, this will begin to
disentangle the effects of plastics versus prenatal stress. Pharmacologic modulation of key nodes in the stress
response pathway will potentially provide insight on appropriate therapies for women in high-risk pregnancies.
Aim 3 will determine the extent of genetic disruptions via transposon insertions induced by early gestational
stress and phthalates in directly exposed germ cells and subsequent generations. These studies will identify
environmental factors that pose greatest risk to genomic integrity and potentially a drug therapy to mitigate
those effects.

## Key facts

- **NIH application ID:** 10245162
- **Project number:** 5R01ES028212-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Diana J Laird
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $287,031
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245162

## Citation

> US National Institutes of Health, RePORTER application 10245162, The intersection of stress and environmental chemicals in germ cell reprogramming (5R01ES028212-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10245162. Licensed CC0.

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