# CIALIS® reverses halogen induced injury to pregnant animals and their offspring

> **NIH NIH U01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $724,864

## Abstract

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 ...

## Key facts

- **NIH application ID:** 9982331
- **Project number:** 5U01ES027697-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** TAMAS Sandor JILLING
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $724,864
- **Award type:** 5
- **Project period:** 2016-09-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982331

## Citation

> US National Institutes of Health, RePORTER application 9982331, CIALIS® reverses halogen induced injury to pregnant animals and their offspring (5U01ES027697-05). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/9982331. Licensed CC0.

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