Industrial accidents, urban environmental disasters and terrorist attacks involving bromine gas (Br2) are of great concern to public safety. Br2 is used extensively in manufacturing and, therefore, needs to be transported and stored in large quantities. Accidental and intentional discharges of Br2 with consequent large number of casualties have been reported. We are only beginning to understand the mechanisms and potential countermeasures of Br2 toxicity and the identification of particularly vulnerable populations is completely lacking. Our preliminary studies show that pregnant mice exposed to 600 ppm Br2 for 30 minutes at gestation day 15 (E15) and returned to room air, exhibit 75% mortality. This mortality rate is considerably higher than what is seen in non-pregnant female or male mice at the same exposure level (25% mortality). Fetuses of surviving mothers are severely growth restricted at E19 and the mothers exhibit symptoms of preeclampsia. Placentae of pregnant mice exposed to Br2 express high levels of the short form of fms-like tyrosine kinase 1 (sFLT1), a known mediator of systemic endothelial dysfunction and preeclampsia. We propose the following hypotheses: 1) Preeclampsia, as a pregnancy-specific condition is responsible for the increased vulnerability of pregnant mothers and their unborn fetuses to Br2 toxicity. 2) Intervention with inhibitors of type 5 cyclic nucleotide-specific phosphodiesterases (PDE5i) will mitigate systemic endothelial dysfunction, which is a shared mechanism of halogen toxicity and preeclampsia; they will save the lives of mothers and improve fetal growth. We are proposing to conduct the following experiments grouped in two well integrated specific aims: SA #1. Identify the mechanisms by which exposure of pregnant mice to Br2 gas (600 or 400 ppm for 30 min) leads to significantly higher mortality than non-pregnant mice and causes fetal growth restriction/fetal demise (FGR/FD) when returned to room air. We propose that maternal mortality and FGR/FD are due to systemic hypoxemia and damage to endothelial NOS (eNOS), causing the placenta to produce anti-angiogenic factors, leading to the development of preeclampsia/eclampsia.SA #2. Investigate the efficacy of post Br2 exposure administration of (PDE5i) to decrease preeclampsia, FGR/FD and mortality in pregnant mice. Following exposure to Br2, tadalafil (1 mg*kg-1*day-1; a PDE5i with a long half-life) or placebo will be administered by gavage every 24 h starting at 1 h post exposure. Maternal death, fetal growth, and hallmark symptoms of systemic endothelial dysfunction and preeclampsia will be measured in pregnant and non-pregnant mice as discussed in SA#1. In summary, this exploratory translational research project will begin delineating the mechanisms of Br2 toxicity in pregnant mice and will test the efficacy of highly promising countermeasures (PDE5i) which are already in clinical trials for the treatment of preeclampsia. Thus, we believe that this project is consistent with the overarching goal of the CounterACT program to design better countermeasures for vulnerable populations.
Bromine is a strong oxidant which is used extensively in manufacturing, as well as stored and transported in large quantities, and accidental and intentional discharges of Br2 with a consequent large number of casualties have been reported. We propose research to follow up on our seminal finding that pregnant women and their unborn fetuses represent a highly vulnerable population to bromine-toxicity. We identified the potential mechanism that renders pregnant women and their fetuses highly vulnerable and we have identified a potential potent countermeasure to be tested.
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