# Mechanisms underlying sex-dependent pregnancy outcomes caused by fetal and maternal genomic instability

> **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $342,643

## Abstract

Adverse pregnancy outcomes can be the consequence of defects in several factors, such fetal or maternal
genetics, environmental exposures, uterine dysfunction, preeclampsia, nutrition, infection, inflammation, and
placental insufficiency. Development of a healthy placenta from trophectoderm precursors enables proper
nutrient, gas and waste exchange between the fetus and mother. Additionally, maternal and placenta-intrinsic
inflammation at the interface must be controlled to protect the fetus. This project addresses how genomic
instability (GIN) during oogenesis and embryogenesis can cause sexually dimorphic pregnancy outcomes,
and how the placenta may be especially susceptible to this condition. Research into this underappreciated
cause of adverse pregnancy outcomes is motivated by findings that female mouse embryos are dramatically
more prone to lethality when bearing certain GIN-causing mutations of DNA replication or repair genes. In one
such model that will be utilized in this project, the female-biased lethality was due to increased susceptibility
to inflammation, whereas male embryos were protected by the anti-inflammatory effects of testosterone.
Preliminary data implicate the placenta as the sensitive tissue underlying the embryonic death. Remarkably,
this sex-biased lethality occurred only if the dam also had a GIN genotype. The goals of this project are to
understand the tissue(s), cells, and mechanisms driving GIN-induced lethal inflammation. This will be
accomplished using the power of mouse genetics, genomics, and embryo manipulation. Aim 1 will test whether
the placenta, the embryo, or both, are responsible for female-biased lethality. We hypothesize that the highly
polyploid trophoblast giant cells may be especially sensitive to compromised DNA replication and GIN,
triggering innate inflammation. Aim 2 addresses why oocytes must come from high GIN mothers for the sex
bias to occur in fetuses bearing the mutant lethal genotype. Preliminary experiments implicate that such dams
produce oocytes with compromised mitochondria, and this hypothesis will be tested using mitochondrial
augmentation and -omics analyses. Aim 3 seeks to identify the molecular basis of lethal embryonic
inflammation, with a focus on triggers of innate immunity. A combination of genetic and molecular assays will
be used to test the hypothesis that nuclear GIN leads to mitochondrial RNA and DNA leakage, activating a
pathway(s) that stimulates transcription of inflammation-driving interferon genes.
Overall, if successful, the results will be relevant for interpreting and addressing individual cases of recurrent
pregnancy loss that may have a basis in intrinsic inflammation during gestation, and provide insights into
underappreciated mechanisms causing adverse pregnancy outcomes including miscarriage and intrauterine
growth retardation.

## Key facts

- **NIH application ID:** 10901862
- **Project number:** 5R01HD107910-03
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** John C Schimenti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $342,643
- **Award type:** 5
- **Project period:** 2022-09-14 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901862

## Citation

> US National Institutes of Health, RePORTER application 10901862, Mechanisms underlying sex-dependent pregnancy outcomes caused by fetal and maternal genomic instability (5R01HD107910-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10901862. Licensed CC0.

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