All ETDs from UAB

Advisory Committee Chair

Sadis Matalon

Advisory Committee Members

Namasivayam Ambalavanan

James Collawn

Gang Liu

Rakesh Patel

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Toxic chemicals may pose an increased threat to vulnerable populations such as pregnant women and their unborn fetuses. The halogen bromine has numerous industrial utilities that include flame retardant, pharmaceutical, insecticide, and bleaching additive production. At room temperature, bromine is a volatile liquid. When the gas is inhaled, bromine causes exposure-dependent acute and chronic pulmonary and systemic injuries that range from mild eye and airway irritation to severe damage to the cardiopulmonary system and other organs, which can lead to death. If exposure is survived, patients still may develop reactive airway disease syndrome and pulmonary fibrosis as well as restrictive and obstructive pulmonary diseases and/or multi-organ failure. Though US census bureau data predicts four percent of American women are pregnant at any given time, there are no studies evaluating acute and chronic sequelae of bromine inhalation in any pregnant model. Exposing pregnant mice at gestational day 14.5 (E14.5) to Br2 (600 ppm for 30 min.) results in 80% mortality over five days. In contrast, there is 35% mortality in males or non-pregnant females (p<0.001). Pregnant mice exposed to Br2 demonstrate increased pulmonary and systemic blood pressures, increased circulating inflammatory cytokines and anti-angiogenic molecules (e.g. sFLT-1). Furthermore, fetuses delivered at E18.5 of surviving Br2-exposed dams exhibit severe fetal growth restriction (FGR) and fetal demise. These data suggest Br2 exposure of pregnant mice induces a state of preeclampsia leading to increased mortality. We have identified two compounds that, when administered post-exposure, ameliorate or abrogate the pregnancy-specific symptoms leading to increased mortality: the orally administered the FDA-approved phosphodiesterase 5 (PDE5) inhibitor, tadalafil, and the subcutaneous delivered VEGF isoform VEGF-121.

Share

COinS