# Multigenerational Effects of Gestational Testosterone Excess

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $469,672

## Abstract

PROJECT SUMMARY
Inadvertent fetal exposure to excess steroids or steroid mimics poses risks to reproductive and metabolic
health in humans. At risk is the offspring whose mother has elevated levels of endogenous or exogenous
steroids during pregnancy for a variety of reasons, including disease states and exposure to environmental
compounds with steroidogenic activity. Experimental manipulation of the fetal steroid environment provides a
powerful tool not only to unravel the mechanisms underlying the development of reproductive dysfunction and
infertility, but also to develop intervention strategies to improve reproduction and prevent transmission of
undesirable traits to subsequent generations. Our studies using sheep as the animal model demonstrated that
prenatal exposure to excess testosterone from days 30-90 of pregnancy leads to reproductive neuroendocrine,
ovarian and metabolic perturbations in the female offspring that recapitulate those seen in women with
polycystic ovary syndrome (PCOS). These perturbations include oligo-anovulation, multifollicular ovarian
morphology, functional hyperandrogenism, and insulin resistance. Furthermore, excess postnatal weight gain
exacerbated the severity of such dysfunctions in female sheep prenatally exposed to testosterone excess. With
mounting evidence supporting that developmentally-programmed traits are transmitted across multiple
generations, elucidating the mechanisms by which reproductive and metabolic dysfunctions are passed on to
the next generation in the sheep model of PCOS may help develop intervention strategies to alleviate adverse
multigenerational effects and improve the health of subsequent generations. Using the day 60 to 90 gestational
testosterone exposure model that allows natural mating (female offspring are not virilized like the 30-90 day
exposure model), this proposal tests the novel hypotheses that: 1) prenatal testosterone excess promotes
epigenetic, molecular, and functional alterations at multiple levels of the reproductive and metabolic systems
that will carry over to subsequent generations, thus contributing to the vertical transmission of disease traits;
and 2) lifestyle modifications via dietary intervention will considerably mitigate expression of these adverse
events and will protect the second-generation (F2) offspring from inheriting several reproductive and metabolic
defects programmed by prenatal testosterone excess and aggravated by increased adiposity. The studies
proposed in this application target the developmental origins of adult disease and focus on a large animal
model of translational relevance that exhibits a developmental trajectory that parallels that of humans. Because
gestational exposure to excess steroids due to maternal disease and/or environmental factors impairs fertility,
the findings from these studies will provide crucial biological information for improving reproduction across
generations and will be of relevance in meeting the scientific missi...

## Key facts

- **NIH application ID:** 9971799
- **Project number:** 1R01HD099096-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Rodolfo C. Cardoso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,672
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971799

## Citation

> US National Institutes of Health, RePORTER application 9971799, Multigenerational Effects of Gestational Testosterone Excess (1R01HD099096-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971799. Licensed CC0.

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