Prenatal diesel exhaust exposure enhances neonatal hyperoxia-induced kidney injury via oxidative stress and lipid disruption

Abstract

Prenatal exposure to diesel exhaust particles (DEP) and postnatal oxygen therapy are both clinically relevant perinatal stressors, but their combined effects on kidney development are not well characterized. Using a rat model (Sprague Dawley, n = 10/group), pregnant dams received DEP via intranasal instillation (500 μg/day in PBS, gestational day 16-21; NIST SRM 2975), and offspring were maintained in either room air or 85 % oxygen chambers from birth through postnatal day 14. At postnatal day 14, kidneys were analyzed by histology, Western blot, ELISA, and LC-MS metabolomics. Offspring that received both prenatal DEP and postnatal oxygen showed more severe tubular injury across sexes, and higher kidney-to-body weight ratios that were driven primarily by significant increases in male offspring, whereas changes in females did not reach statistical significance. Kidney injury molecule-1 (KIM-1) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were increased, and 8-OHdG showed a significant interaction between DEP and oxygen exposure. Interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) were elevated by both DEP and oxygen, indicating additive effects. Serum cystatin C, a marker of renal dysfunction, was also increased in all exposed groups and was highest in the dual-exposure group. Cystatin C levels showed strong positive correlations with renal levels of IL-1, IL-6, and TNF-α. Untargeted metabolomics revealed changes in glycerophospholipid metabolism that were specific to the group exposed to both DEP and oxygen. These results suggest that prenatal DEP exposure may increase renal sensitivity to postnatal oxidative stress, pointing to a time-sensitive window of vulnerability during early kidney development.

Keywords: Developmental nephrotoxicity; Diesel exhaust particles; Environmental toxicology; Kidney injury molecule-1; Metabolomics; Oxidative stress.