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 SDB incidence, and its significant morbidities, our studies will be essential for identifying underlying mechanisms that can be targeted by novel therapies to prevent or correct SDB in reprogrammed adults.
The association between sleep disordered breathing during pregnancy, and adverse maternal and neonatal outcomes has only recently become appreciated, so virtually nothing is known about whether there are negative physiological consequences that last into adulthood. In an animal model, adult offspring born from mothers exposed to intermittent low oxygen (hallmark feature of sleep disordered breathing) have chronic brain inflammation that impairs neurons controlling breathing, which consequently may predispose adult offspring to unstable breathing during sleep. Our proposed studies will investigate potential underlying causes, as well as a number of novel treatment strategies that can be delivered either during pregnancy as a preventative measure, or in adulthood, to cure respiratory problems created by maternal sleep disordered breathing, a condition which affects hundreds of thousands of pregnant women each year in the U.S. alone.
