The halogen bromine (Br2) is used as water disinfectant, for bleaching fibers, for manufacturing antiepileptic drugs, dyestuffs, flame-retardants, insecticides, drilling fluids, and gasoline additives. When inhaled, it causes exposure-level-dependent acute and chronic pulmonary and systemic injuries ranging from mild eye and airway irritation, to significant damage to cardiopulmonary system and other organs, which can lead to death. Survivors may develop reactive airway disease syndrome, pulmonary fibrosis as well as restrictive and obstructive pulmonary diseases. Presently, there are no studies evaluating acute and chronic sequelae of Br2 inhalation in pregnant rodent and non-rodent models, even though US census bureau data predicts two of every 100 people in the US being pregnant. Exposure of pregnant mice at gestational day 15 (E15) to Br2 (600 ppm for 30 min.) results in 75% mortality over four days, in contrast to 25% mortality in males or non-pregnant females (p<0001). When delivered at E19, fetuses of surviving Br2-exposed mice exhibit severe fetal growth restriction (FGR) and fetal demise (FD). Placentas are poorly developed and express increased levels of short-FMS-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic mediator and biomarker of both preeclampsia and pulmonary hypertension. When born naturally, none of the fetuses survive. Oral administration of an FDA- approved type 5 cyclic nucleotide-specific phosphodiesterase inhibitor (PDE5i; tadalafil) to the dams post- exposure, dramatically improved maternal survival, fetal growth restriction and neonatal survival. We hypothesize that brominated intermediates, formed by the reaction of Br2 and HOBr with plasmalogens cause injury to the endothelium and the placenta, inducing the release of vasoconstrictor and anti-angiogenic mediators which in turn mediate pulmonary vasoconstriction, increased pulmonary artery pressure and right ventricular dysfunction. Tadalafil restores pulmonary and uterine vasodilation, preserves heart function and improves uterine/placental blood supply resulting in maternal and fetal survival. We will test these proposed mechanisms and we will perform the necessary efficacy studies to identify the optimum therapeutic regimen of tadalafil to decrease maternal morbidity and mortality, improve fetal growth restriction and increase fetal survival when administered orally post exposure.
Specific Aim #1. To test the hypothesis that exposure of pregnant mice to Br2 at E15 causes extensive pulmonary injury as well as systemic endothelial injury, placental injury, pulmonary hypertension, right heart failure resulting in maternal mortality, fetal growth restriction and fetal demise/stillbirth.
Specific Aim #2 : To identify the sequence of events and mechanisms involved in the development of maternal vasoconstriction, pulmonary hypertension and right heart failure.
Specific Aim #3. To investigate the efficacy of post halogen exposure administration of tadalafil to decrease maternal and fetal death and morbidity and to develop a rabbit (non-rodent) model of Br2 toxicity in pregnancy.
We have discovered that pregnant mice are highly susceptible to bromine. Tadalafil, an FDA approved agent, reverses injury to pregnant mice and offsprings when administered after Br2 exposure. We will investigate the mechanisms involved and identify the optimum way of delivering tadalafil.
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