Differential Cardiometabolic Impacts of Maternal Ozone Exposure in Adult Long-Evans Offspring
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Cardiovascular disease (CVD) and metabolic disorder are both substantial contributors to global mortality, with their pathologies closely intertwined. Exposure to ambient air pollutants (AAPs) has been shown to negatively impact offspring cardiometabolic health, linked with the development of cardiac hypertrophy and dyslipidemia, among others. While environmental factors influence the pathogenesis of cardiometabolic conditions, adverse exposures during critical developmental windows may also contribute to disease risk. We have previously shown that gestational exposure to the AAP ozone (O3) compromises fetal growth and predisposes offspring for susceptibility to metabolic and pulmonary perturbances later in life. However, the cardiovascular consequences of this gestational O3 exposure remain largely under-characterized. Considering evidence linking early life exposures to particulate matter and other AAPs to postnatal cardiovascular dysfunction, herein, we sought to explore whether similar phenotypes were present in offspring from O3 exposed dams. We hypothesized that offspring born to O3 exposed dams would have worsened cardiovascular function as they age into adulthood, with a differential response across sexes. To evaluate the cardiovascular and metabolic consequences of gestational O3 exposure, 12-week-old timed-pregnant Long-Evans rats were exposed to either filtered air or 0.8 ppm O3 for 4 hours/day on gestation days (GDs) 5 and 6. Following weaning, male and female offspring were monitored for cardiometabolic health until ~5 months of age. Maternal O3 exposure did not result in changes to most of the metabolic measurements collected before 4 months of age (body weight, food intake, body composition, glucose tolerance, blood pressure). However, indirect calorimetry testing at ~4 months old, revealed that offspring born to O3 exposed dams had altered respiratory exchange ratio. This effect differed by sex - increased in females and decreased in males. Furthermore, histological assessment of adipose tissue revealed that female offspring experienced adipocyte hyperplasia in the retroperitoneal depot. M-mode dobutamine stress echocardiography at ~5 months, as well as cardiac histology, revealed male offspring born to O3 exposed dams had altered cardiac structure and function, including thickening of the left ventricular wall, increased ejection fraction, and increased fractional shortening. For female offspring born to O3 exposed dams, pulsed-wave doppler assessment of transmitral valve flow revealed an increased myocardial performance index due to decreased aortic ejection time. Based on these findings, we performed RNAseq on archived hearts from GD 21 fetuses. This analysis revealed sexually dimorphic effects of gestational O3 exposure on cardiac gene expression, supporting the hypothesis that this exposure may disrupt cardiac development. Collectively, these results demonstrate maternal exposure to O3 is detrimental to offspring cardiovascular development, extending our previous findings, demonstration that peri-implantation O3 exposure results in multi-organ dysfunction in adult offspring. This abstract does not reflect US EPA policy.