Background Early exposure to stress negatively impacts neurodevelopmental outcome. All preterm infants admitted to the NICU are exposed to the stress of maternal separation. In the rat, perinatal stress alters cerebral histone covalent modification and increases the expression of key glucocorticoid receptor (GR) splice variants. Erythropoietin (EPO) supplementation has been shown to exibit neuroprotective effects and alter histone covalent modifications.
Hypothesis We therefore hypothesized that EPO supplementation to pups stressed during the perinatal period would alter cerebral histone covalent modification and GR expression.
Design/Methods Sprague-Dawley rat pups were removed from their dams, hand-fed rat milk substitute during the day, and returned to dams during the night for maternal feedings during postnatal days 3 to 8. Pups were also given either erythropoietin (5,000 U/kg/day) or saline (50 μL/day). Pups were killed on postnatal day 10 and brains harvested. Histone H3 lysine (K) methylation and acetylation were assessed by Western blot analysis. mRNA for total glucocorticoid receptor (GR) and the GR splice variants 1.5, 1.6, 1.7, 1.10, and 1.11 was quantitated using real-time RT-PCR.
Results In males, supplementation with erythropoietin decreased both histone H3 acetylation and methylation (dimethyl-K4 85.7 ± 2%*, dimethyl-K9 74.3 ± 1.9%*, acetyl-K9 79.0 ± 1.6%*, and acetyl-K18 84.5 ± 2.4%*). EPO supplementation in males also resulted in decreased mRNA expression of the glucocorticoid splice variants 1.5, 1.7, and 1.11. (79.2 ± 3.9%*, 52.4 ± 0.6%*, and 64.9 ± 8.3%*). Interestingly, in females, EPO supplementation resulted in an increase in histone H3 acetylation (acetyl-K14 128.1 ± 4.2%*, acetyl-K18 108.3 ± 2.5%*) (*n = 3, p < .05).
Conclusions EPO supplementation decreases cerebral histone covalent modification and GR receptor splice variant mRNA expression in perinatally stressed male rat pups. EPO increased cerebral histone acetylation in stressed female pups. Perinatal stress alters patterns of cerebral histone covalent modification and increases the expression of GR splice variants. We speculate that supplementation with erythropoietin moderates this response, thereby limiting the long-term detrimental neurodevelopmental effects of perinatal stress. Importantly, these effects occur in a gender-specific manner.
Supported by the CHRC.
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