Bromine Inhalation in Pregnant Mice Induces Systemic and Pulmonary Hypertension, Fetal Growth Restriction, Heart Failure and Death
Authors: Lambert James Andrew , Carlisle Matthew , Lam Adam , Aggarwal Saurabh , Zaky Ahmed , Dell'Italia Louis , Bradley Wayne , Jilling Tamas , Matalon Sadis 
Published: November 2023

Inhalation of caustic and oxidant gas and vapor like the halogen bromine (Br2) may pose an increased threat to vulnerable populations such as pregnant women and their unborn fetuses. C56Bl/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 controls kept at room air (P‐AIR and NP‐AIR). At E19, P600 exhibited 75% mortality vs the 36% seen in NP600 (P<0.001; Mantel Cox). We hypothesized that exposure to Br2 via inhalation results in systemic endothelial dysfunction and a vasoconstrictive environment. We further hypothesized that in pregnant females the ensuing placental injury 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 (TDF) therapy. FGR was observed following Br2 exposure (fetal weights 1.11±0.04 g in P‐AIR vs 0.47±0.02 g in P600; P<0.001;ANOVA) and mitigated after 2mg/kg/day TDF treatment (fetal weight 0.74±0.02 g in P600 + TDF (P<0.001 vs P600; ANOVA)). Placentae had reduced junctional zones and absent glycogen‐containing cells in P600 compared to P‐AIR. Placentae also expressed increased levels of short FMS‐like tyrosine kinase 1 (sFLT1) in P600 vs P‐AIR. At E19 cGMP levels (per g of tissue) in the lungs were 8.8±0.9 pmol/g in P‐AIR, 3.4±0.4 pmol/g in P600 and 6.6±0.8 pmol/g in P600+TDF (P<0.001 P‐AIR vs P600 and P<0.05 P600 vs P600+TDF). Similar changes were seen in aorta but due to small sample size, data is not shown. Additionally, bronchoalveolar lavage fluid (BALF) protein content, plasma glutathionylated lipids and plasma inflammatory cytokines (IL‐1β, IL‐6, KC) were elevated in P600 vs P‐AIR and reduced in P600+TDF vs P600. Utilizing echosonography and pulsed‐wave Doppler of pulmonary artery flow, right ventricle (RV) pressures were estimated as 33.8±1.0 mmHg in P‐AIR vs 38.5±1.5 mmHg in P600 as compared to 29.6±1.3 mmHg in P600+TDF (P<0.05 P‐AIR vs P600, P<0.01 P600 vs P600+TDF). Mean arterial pressures (MAP) measured by solid‐state intra‐arterial catheter were 65.9±3.3 mmHg in P‐AIR vs 82.6±82.6 mmHg in P600 as compared to 37.51±4.6 mmHg in P600+TDF (P<0.01 P‐AIR vs P600; P<0.001 P600 vs P600+TDF; ANOVA). All data shown are mean ± S.E.M. and n>3. This study implicates Br2 inhalation‐induced vascular dysfunction in pregnancy leading to decreased pulmonary and aorta cGMP concentrations as well as increased systemic and pulmonary blood pressures. Tadalafil significantly increases cGMP levels and diminishes the deleterious effects of Br2 inhalation on mother and fetus. Tadalafil is a potentially safe and effective countermeasure for Br2 inhalation injury in pregnancy.

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Funded By NIEHS grants 1R21ES026829‐01 and 1U01ES026458‐01A1