161 - Bromine Exposure in Pregnant Mice May Reduce VEGF Signaling Via Increased Circulating VEGF Decoy Receptor sFLT-1

Abstract

Inhalation of oxidant gas and vapor like the halogen bromine (Br2) may pose an increased threat to pregnant women and their unborn fetuses. We recently published that pregnant (P) C57Bl/6 mice exposed to 600ppm Br2 for 30 minutes on gestational day 14.5 (E14.5) exhibited increased mortality, lung injury, and blood pressure at E18.5 when compared to similarly exposed non-pregnant (NP) mice. Additionally, fetuses of Br2-exposed pregnant mice displayed severe growth restriction, which cumulatively indicated a preeclampsia-like phenotype. Administration of the phosphodiesterase 5 (PDE5) inhibitor tadalafil abrogated or significantly mitigated these effects in Br2-exposed pregnant mice but had no effect on non-pregnant counterparts. We hypothesize that exposure to Br2 via inhalation in pregnant mice results in placental damage and subsequent release of anti-angiogenic molecules into maternal circulation resulting in systemic endothelial dysfunction and a vasoconstrictive environment mediated by dysfunctional VEGF signaling. Firstly, we have identified significant increases at 0.5h post-Br2 exposure of circulating brominated fatty acids and fatty acid aldehydes (2-BrPA and 2-BrPALD) as well as their glutathionylated species at 6h. These may serve as potential biomarkers and/or mediators of Br2-inhalation induced systemic injury. Furthermore, preliminary results indicate aortas incubated ex vivo in the presence of 2-BrPA and 2-BrPALD are more sensitive to the vasoconstricting agent phenylephrine and less sensitive to the vasodilator acetylcholine. Secondly, utilizing time-course measurements, we have identified increases in the circulating VEGF decoy receptor sFLT-1 beginning at 72h post-exposure in pregnant mice. No increase is observed in similarly exposed non-pregnant mice (PBr272h 7280.3 ± 1592 vs NPBr272h 1233.5 ± 1063 pg/mL p≤0.001). Additionally, this time point also coincides with a pregnancy specific increase in lung edema/injury as evidenced by lung wet:dry weight ratios (P Br272h 4.68 ± 0.10 vs NP Br272h 4.22 ± 0.04 p≤0.05). This study implicates diminished VEGF signaling in pregnancy specific Br2 inhalation injury contributing to increased blood pressures, lung injury and subsequent mortality.