340 - Bromine Inhalation in Pregnant Mice Induces Systemic and Pulmonary Hypertension, Fetal Growth Restriction, Heart Failure, and Death

Abstract

Inhalation of oxidant gas and vapor like the halogen bromine (Br2) may pose an increased threat to pregnant women and their unborn fetuses. C57Bl/6 pregnant and non-pregnant mice were exposed to 600ppm Br2 for 30 minutes (P600 and NP600) at embryonic day 15 (E15) and were compared to air controls (P-AIR and NP-AIR). At E19, P600 exhibited 75% mortality vs 36% seen in NP600. We hypothesized that exposure to Br2 via inhalation results in systemic endothelial dysfunction and a vasoconstrictive environment. We further hypothesized the ensuing placental injury in pregnant females induces production of anti-angiogenic molecules and inflammation, leading to escalation of vascular dysfunction, increased pulmonary and systemic blood pressures, fetal growth restriction (FGR), and death that may be mitigated by tadalafil (TAD) therapy. FGR was observed following Br2 exposure and mitigated after 2mg/kg/day TAD treatment. Placentae had reduced junctional zones and absent glycogen containing cells in P600 vs P-AIR. Placentae also expressed increased levels of short FMS-like tyrosine kinase 1 (sFLT1) in P600. At E19, cGMP levels in the lungs decreased in P600, and were mitigated by TAD. Similar changes were seen in the aorta. Additionally, bronchoalveolar lavage fluid protein content, glutathionylated lipids, and inflammatory cytokines (IL-1Β, IL-6, KC) in plasma were elevated in P600 and reduced in P600+TAD. Right ventricle pressures were increased in P600 and mitigated by TAD. Systemic blood pressures measured by intra-arterial catheter also increased in P600 and were mitigated by TAD. We have identified circulating brominated fatty acids and fatty acid aldehydes (2-BrPA and 2-BrPALD) as potential mediators of Br2-inhalation induced systemic injury. When treated with 2-BrPA and 2-BrPALD ex vivo, arteries of pregnant mice exhibited increased sensitivity to phenylephrine-induced vasoconstriction as well as a decreased sensitivity to acetylcholine-induced vasodilation. This study implicates Br2 inhalation-induced vascular dysfunction augmented in pregnancy as a significant contributor to increased mortality. Additionally, tadalafil diminishes deleterious effects of Br2 inhalation on mother and fetus. Tadalafil is a potentially safe and effective countermeasure for Br2 inhalation injury in pregnancy.