Differential Metabolic, Thermal, and Pulmonary Responses to Early Life Ozone Exposure in Male and Female Rats.
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The essential role that early life events (i.e., intrauterine growth restriction) and environmental exposures (i.e., air pollution) play in development of childhood asthma and obesity are only partly understood. Notably, asthmatic children who develop obesity through adolescence have poorer disease outcomes. In our previous studies we showed that exposure of Long-Evans rats to the oxidant air pollutant, ozone (O3), during implantation [gestational days (GD) 5 and 6; 0.8 ppm x 4h] resulted in growth restriction at GD21. The aims of this study were to determine whether gestational +/- repeated peri-adolescent O3-exposure (0.4–0.8 ppm x 4h; once/week at 5, 6, and 7 weeks-of-age) would alter offspring metabolism, body, or lung growth, and acute thermal or pulmonary responses to O3. Using 2-way ANOVA with Dunnett’s post hoc correction, responses in males (M) and females (F) were evaluated separately; all O3-exposed groups were compared to controls [air-exposed dams + PN-Air-(x3)] of the corresponding sex. By postnatal (PN) day 45, results showed that in males, dam O3-exposure was associated with augmented body “height” (skull base-to-tail head) and increases in serum triglyceride, and cholesterol levels; but not body weight, weight adjusted by height (gm/cm), or corrected lung (fixed) volume (mL/cm height x100%). PN-O3x3 exposures were associated with increased HOMA-IR ratios and further increases in cholesterol. In females, dam O3-exposure was associated with lower lung volumes and increased serum cholesterol; while PN-O3x3 exposure was associated with reduced weight/height (gm/cm). For both sexes, the degree of acute hypothermia was altered in association with both dam- and especially PN-O3 exposures; whereas lung injury (e.g., increased protein leakage) and inflammation (e.g., neutrophils) in lung lavage fluid, were increased chiefly by PN-O3 exposure. Particularly in males, lesser inflammatory responses were observed in O3+O3x3 rats (e.g., reduced KC-GRO and IL-6 cytokine levels) compared to Air+O3x3 rats. Conversely, lavage fluid TNFalpha concentrations were increased only in the O3+O3x3 males. Taken together, data suggest that O3 exposure during gestation played a greater role in predisposing offspring to dyslipidemia, whereas peri-adolescent exposure dominated the acute hypothermia and inflammatory responses. Importantly, males exposed to both gestational and postnatal O3 appeared to (A) develop greater dyslipidemia (a precursor of metabolic syndrome) and (B) altered lung innate inflammatory responses -- potentially influencing TH-1 to TH-2 balance (a precursor to allergic asthma) later in life. (This abstract does not reflect USEPA policy).