Maternal ozone exposure and differential cardiometabolic outcomes in aging male and female offspring

Abstract

Fetal development is a vulnerable life stage for exposure to environmental stressors. Gestational exposure to ozone (O₃) has been shown to compromise fetal growth, predisposing offspring to increased risk of pulmonary and metabolic dysfunction later in life. However, the cardiovascular consequences of maternal O₃ exposure on offspring health remain uncharacterized. Herein, pregnant Long-Evans rats were exposed to 0.8 ppm O₃ for 4 h each day on gestation day (GD) 5 and 6. Following weaning, male and female offspring were monitored for cardiometabolic health for up to ∼5 months of age. Although there were little-to-no changes in most metabolic endpoints (e.g., growth, food intake, body composition, or glucose tolerance), offspring from O₃ exposed dams had an altered respiratory exchange ratio at ∼4 months old that differed by sex. Furthermore, female offspring had adipocyte hyperplasia in the retroperitoneal depot, effects that were not evident in male offspring. Males from O₃-exposed dams had altered cardiac structure and function, including left ventricular wall thickening and increased ejection fraction and fractional shortening. Females from O₃-exposed dams, on the other hand, had decreased myocardial performance attributed to shortened aortic ejection. RNAseq on hearts from GD 21 fetuses revealed sexually dimorphic effects of maternal O₃ exposure on cardiac gene expression, consistent with altered structure and function that was present in adulthood. Collectively, these findings demonstrate that peri-implantation O₃ exposure increases the risk of multiple adverse effects, including cardiac dysfunction, in adulthood.