Respiratory vulnerability and brainstem damage induced by early ethanol exposure during intermittent hypoxia in rats, with selective neuroprotection by fish oil

Early ethanol exposure during development disrupts respiratory control, reduces central omega-3 fatty acid availability, and promotes neuronal degeneration in brainstem nuclei involved in autonomic regulation. Using a rat model corresponding to the human third gestational trimester (postnatal days 3–9), we examined the effects of early, binge-like ethanol exposure and the potential neuroprotective role of fish oil, a major omega-3 source, on ventilatory responses to normoxia and intermittent hypoxia, as well as on cell degeneration within the respiratory network. Rat pups received ethanol (2.0 g/kg) and fish oil (720 mg/kg) on postnatal days 3, 5, and 7. On postnatal day 9, pups were exposed to an intermittent hypoxia protocol following ethanol administration. Ventilatory parameters were assessed, and pyknotic cells and cleaved caspase-3–positive cells were quantified in medullary raphe nuclei and the nucleus of the solitary tract. Early ethanol exposure depressed respiratory frequency under normoxia, attenuated the hypoxic ventilatory response, and reorganized apnea expression across experimental conditions. Both ethanol exposure and intermittent hypoxia increased cell degeneration in medullary raphe nuclei and the nucleus of the solitary tract, with additive or synergistic effects depending on the nucleus. Fish oil supplementation modestly enhanced ventilation in control pups under normoxia but did not rescue ethanol-induced ventilatory impairments. Notably, fish oil selectively attenuated hypoxia-induced cell degeneration in the nucleus of the solitary tract, reducing both pyknotic and cleaved caspase-3–positive cells. These findings demonstrate that brief, binge-like ethanol exposure is sufficient to disrupt early-life respiratory control and promote brainstem cell degeneration, while identifying nucleus-specific neuroprotection by omega-3 supplementation against hypoxia-related injury.