Abstract
Preterm infants are at significantly increased risk for lifelong neurodevelopmental disability with male offspring disproportionately affected. Corticosteroids (such as betamethasone) and magnesium sulphate (MgSO4) are administered to women in preterm labor to reduce neurologic morbidity. Despite widespread use of MgSO4 in clinical practice, its effects on adult offspring are not well known nor have sex-specific differences in therapeutic response been explored. The objective of our study was to examine the long-term effects of perinatal neuroinflammation and the effectiveness of prenatal MgSO4/betamethasone treatments between males and females in a murine model via histologic and expression analyses. Our results demonstrate that male but not female offspring exposed to intrauterine inflammation demonstrated impaired performance in neurodevelopmental testing in early life assessed via negative geotaxis, while those exposed to injury plus treatment fared better. Histologic analysis of adult male brains identified a significant reduction in hippocampal neural density in the injured group compared to controls. Evaluation of key neural markers via qRT-PCR demonstrated more profound differences in gene expression in adult males exposed to injury and treatment compared to female offspring, which largely showed resistance to injury. Prenatal treatment with MgSO4/betamethasone confers long-term benefits beyond cerebral palsy prevention with sex-specific differences in response.
Highlights
Infants born preterm are at increased risk of neurologic injury resulting in neurodevelopmental disability, a global term encompassing varying degrees of neurologic impairment[1]
Dams that received lipopolysaccharide (LPS) exhibited significantly lower litter viability; 100% of litters survived with phosphate buffered saline (PBS) and PBS + MgSO4/betamethasone vs. 63% with LPS and 75% with LPS + MgSO4/betamethasone (ANOVA P < 0.005)
There was no difference in the number of offspring per litter assessed on post-natal day 5 with the exception of PBS vs. PBS + MgSO4/betamethasone control groups
Summary
Infants born preterm are at increased risk of neurologic injury resulting in neurodevelopmental disability, a global term encompassing varying degrees of neurologic impairment[1]. Human and animal studies demonstrate that the type and severity of neurologic injury associated with preterm labor varies between genders, with increased susceptibility in males[10,11,12]. Studies using a murine model have provided insight into the molecular mechanisms of brain injury related to pre-term birth[12,22,23,24]. These studies have demonstrated the effects of in utero neuroinflammation including reductions in hippocampal volume that are detectable in adolescence and analysed sex-specific differences with notation of a greater degree of injury in male offspring[12]. Whether MgSO4 and corticosteroids reduce these negative outcomes in experimental adult animals and if there is a sex-specific difference in their response has not been tested
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