Diesel Exhaust Exposure and N-acetyl-cysteine Supplementation In-utero and Atherosclerotic Lesion Progression in Hyperlipidemic Mice
MetadataShow full item record
Background: Ambient air pollution exposures have consistently been found to be positively associated with cardiovascular morbidity and mortality. Fine particle air pollution (PM2.5), largely derived from diesel exhaust (DE) emissions, have been emphasized as having the most significant effect on cardiovascular health. PM2.5 exposure during pregnancy can have deleterious effects on fetal development, decrease birth weight, and is associated with an increased risk of later life metabolic diseases. The adverse intrauterine conditions may also promote risk of atherosclerosis in adulthood. The mechanism of PM2.5-mediated effects remains unclear, but there is extensive evidence for the generation of reactive oxygen species and ensuing oxidative stress as a central driver of these observations. N-acetylcysteine is an antioxidant and precursor for glutathione (GSH), the major determinant of intracellular reductive potential. In this study, we investigate the effect of DE exposure and NAC supplementation in-utero on adult susceptibility to atherosclerosis. Methods: Female 8- 16 week old ApoE-/- mice (n= 35) were time-mated to ApoE-/- males. Pregnant females were randomly sorted to a treatment group: Diesel exhaust (~300 μm3 PM2.5 for 6 hours/day, 5 days/week) and control water (DC), diesel exhaust and NAC (500 mg/kg/day) (DN), filtered air and NAC (FN), or filtered air and control water (FC). Females were exposed during gestation only and were transferred with their pups to filtered air with control water at birth. All surviving offspring (n=190) were weighed each postnatal week until 16 weeks. At 8, 12 and 16 weeks, plasma was collected for measurement of total cholesterol, total triglyceride, HDL, LDL, and VLDL cholesterol and triglyceride fractions. Mice were sacrificed at 16 weeks. Urine was collected at 16 weeks for determination of 8-isoprostane. DNA from livers was isolated for assessment of 8-hydroxy-deoxyguanosine levels. mRNA from liver, lung, and aortas was extracted to measure expression of heme oxygenase-1 (HO-1) and glutamate cysteine ligase modifying and catalytic subunits (GCLm and GCLc). Aortic sinuses were processed for histology and imaged to assess lesion progression. Differences among treatment groups from the FC group were analyzed using ANOVA. Males and females in each treatment group as well as litter generation aortic lesion areas were separately analyzed. Results: The DC dams had significantly smaller litters than FC dams and there was a trend toward higher mortality in the DC group. Week 1 mean weights for the FC, FN, DC, and DN treatment groups were 4.59±0.3 g, 5.13±0.4 g, 4.45±0.38 g, and 5.84±0.4 g, respectively. Weight growth rate in weeks 1- 8 were: FC= 0.23±0.05 g, FN= 0.38±0.13 g, DC= 0.45±0.16 g, and DN= 0.12±0.09 g. There were no week 8-16 weight gain or final weight significant differences among treatment groups. No major trends were observed in 8, 12, and 16 week lipid profiles among treatment and sex groups. Statistical significance was not observed from the results of 8-OHdG, 8-isoprostanes (urine and liver), or GCLm, GCLc, and HO-1 mRNA expression analyses. Mean aortic lesion areas were not different among treatment groups. Combined offspring from dams second litters had significantly decreased aortic lesion area means compared to first litter offspring. Comment: The results of this research suggest that in utero DE exposure and NAC supplementation does not influence later life redox homeostasis or the risk for increased atherosclerosis progression. Further studies should be conducted in order to fully elucidate the effects of DE on the in utero environment, the pathology of offspring mortality, and of litter generation and maternal characteristics on atherosclerotic development.
- Nutritional sciences