# Signaling mechanisms of gene-environment interactions in female reproductive

> **NIH NIH R21** · UNIVERSITY OF CINCINNATI · 2022 · $243,000

## Abstract

Project Summary/Abstract
Congenital anomalies of the female reproductive tract (FRT) occur in approximately 5% of live birth in females.
These conditions are congenital, but often go undetected until puberty when the patients fail to menstruate and
suffer periodic lower abdominal pain; if left untreated, they lead to infertility and death during pregnancy or
childbirth. The anomalies have complex clinical presentations with the etiology still poorly understood. Given that
FRT anomaly has both familial and sporadic cases, the causative agents are likely to be complex, involving
genes, environmental factors, or both. To date, the multifactorial etiology and the mechanisms of gene-
environment interactions in congenital FRT anomalies are largely unexplored. We have recently identified
Map3k1 loss-of-function as a novel genetic condition of congenital FRT anomaly - Map3k1 inactivation in mice
is associated with developmental FRT defects and infertility in females. Map3k1 encodes a protein kinase, an
upstream regulator of the MAPK pathways that crosstalk with diverse environmental signals and developmental
pathways. We have shown that Map3k1 loss-of-function could aggravate the developmental toxicity of dioxin, a
ubiquitous environmental pollutant. Moreover, dioxin is also a reproductive toxicant that induces FRT defects
similar to those observed in the Map3k1-null mice. In the current proposal, we will test the hypothesis, supported
by preliminary evidence, that Map3k1 mutation plus dioxin constitute the multifactorial etiology that converges
on WNT inhibition to cause congenital FRT anomalies. We will use an in vivo genetic approach to examine
whether Map3k1 mutation plus dioxin exposure potentiate the incidence and/or the severity of FRT defective
phenotypes, whether the dioxin receptor, Ah receptor (AHR), mediates FRT toxicity, and whether the gene-
environment interactions repress WNT activity. We will combine mouse genetics, molecular histopathogenesis,
and laser capture microdissection coupled with global gene expression profiling to delineate the biological
processes and molecular pathways affected by genetic and environmental insults in FRT development. We aim
to understand the molecular details of how gene-environment interactions contribute to congenital female
reproductive anomaly, with the long-term future goal of using this knowledge to prevent and treat this prevalent
devastating disease affecting women’s health and reproductivity.

## Key facts

- **NIH application ID:** 10448935
- **Project number:** 1R21ES033342-01A1
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** YING XIA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,000
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448935

## Citation

> US National Institutes of Health, RePORTER application 10448935, Signaling mechanisms of gene-environment interactions in female reproductive (1R21ES033342-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10448935. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*