# Fetal reprogramming by gestational intermittent hypoxia impairs respiratory neuromotor control in adult offspring

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $651,088

## Abstract

PROJECT SUMMARY
The in utero environment, and in particular, maternal immune activation, is well-known to permanently reprogram
critical fetal physiological systems, but this has been poorly evaluated in the context of respiratory neural control.
Intermittent hypoxia (IH), a hallmark of sleep disordered breathing (SDB), causes both central and peripheral
inflammation, and we have recently begun to appreciate that maternal SDB during pregnancy has profound
negative consequences to the newborn. However, to date, virtually nothing is known regarding whether these
detriments extend into adulthood. Further, it is unknown whether maternal IH is sufficient to cause fetal
reprogramming, or if the adult offspring respiratory control system is a target. Strikingly, obstructive sleep apnea
(OSA), a form of SDB, appears to be heritable, but specific predisposing gene mutations (beyond those causing
craniofacial abnormalities) have not been identified, indicating a likely role for epigenetic inheritance. Epigenetic
alterations underlie many forms of heritable cellular memory including those regulating the innate immune
response, suggesting the intriguing possibility that heritable susceptibility for SDB may be passed from mother
to offspring in utero via epigenetic reprogramming of the fetal immune system. The overarching hypothesis
guiding this work is that gestational intermittent hypoxia (GIH) predisposes adult offspring to SDB themselves by
epigenetically modifying the activities of CNS resident innate immune cells (microglia). Using a rodent model of
GIH, our preliminary data suggest that adult GIH offspring have increased central apneas during presumptive
sleep and impaired compensatory plasticity in response to recurrent reductions in respiratory neural activity.
GIH-induced increases in central apneas is exacerbated by exposure to chronic IH, and compensatory
responses to recurrent apneas is restored by local administration of anti-inflammatory drugs (Aim 1), suggesting
an essential role for neural inflammation in GIH impairments. Moreover, our preliminary data suggest that
microglial responses to an immune system challenge are exaggerated (“primed”) in adult GIH offspring,
consistent with histone mark enrichment at primed inflammatory genes in microglial cultures exposed to hypoxia.
Thus, we hypothesize that GIH primes inflammatory gene transcription by altering the microglial methylome (Aim
2). Our studies will test several strategies to reverse respiratory control impairments caused by fetal
reprogramming of innate immune cells (Aim 3). If our hypotheses are correct, these studies will identify for the
first time that gestational IH: 1) creates life-long deficits in compensatory respiratory neuroplasticity triggered by
recurrent neural apnea, 2) predisposes to unstable breathing in adulthood, and 3) creates life-long, chronic
microglial inflammation associated with epigenetic changes in the microglial methylome. Given the pathological
rise in adult...

## Key facts

- **NIH application ID:** 9859466
- **Project number:** 5R01HL142752-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Tracy L Baker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $651,088
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859466

## Citation

> US National Institutes of Health, RePORTER application 9859466, Fetal reprogramming by gestational intermittent hypoxia impairs respiratory neuromotor control in adult offspring (5R01HL142752-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9859466. Licensed CC0.

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