# Pulmonary implications of perinatal acetaminophen exposure

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $391,348

## Abstract

PROJECT SUMMARY
Acetaminophen (APAP)is one of the most commonly used analgesics in the world, andoverwhelmingly
perceived to be safe. This perception has contributed to ubiquitous exposures during gestation and among
newborns in the neonatal intensive care unit. These exposures occur during critical windows of human
development where pre-clinical and clinical data demonstrating safety are lacking. Alarmingly, clinical data
support the hypothesis that the developing lung may be adversely affected by perinatal APAP exposures. The
toxicity of APAP is dependent on its conversion by the xenobiotic-metabolizing enzyme CYP2E1 the
mitochondrial toxin N-acetyl-para-benzo-quinone imine (NAPQI). Our preliminary data demonstrate that
pulmonary CYP2E1 expression peaks during the saccular stage of development and is limited to the
myofibroblast. Additionally, we show that postnatal APAP exposures induce Cyp2e1 expression in the late
saccular/early alveolar stage lung. Consistent with CYP2E1 expression, we show that the developing lung is
susceptible to APAP-induced injury. These preliminary data have led us to develop the following hypothesis:
The saccular/early alveolar stage lung is susceptible to APAP-induced injury due to developmentally-
regulated pulmonary CYP2E1 expression. We propose three specific aims to test this hypothesis. In Aim 1,
we will test the hypothesis that in utero APAP exposures during the saccular stage of lung development injure
pulmonary myofibroblasts and disrupt alveolarization. In Aim 2, we will test the hypothesis that postnatal APAP
exposures during the late saccular/early alveolar stage induce lung CYP2E1 expression causing oxidative
stress and increase sensitivity to injury. In Aim 3, we will test the hypothesis that inhibiting TLR9/NFκB innate
immune signaling will attenuate APAP-induced newborn lung injury. Our collaborative team bridging
developmental pulmonary biology, physiology, immunology and mitochondrial/oxidative stress biology is well
positioned to fill critical gaps in our understanding of the developmentally-regulated, cell-type specific CYP2E1
expression and APAP-induced lung injury. These studies will help determine the safety profile of APAP to
inform both maternal use and newborn exposures while identifying therapeutic targets to limit adverse effects.
into

## Key facts

- **NIH application ID:** 10808190
- **Project number:** 5R01HD107700-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Clyde Jason Wright
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $391,348
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808190

## Citation

> US National Institutes of Health, RePORTER application 10808190, Pulmonary implications of perinatal acetaminophen exposure (5R01HD107700-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10808190. Licensed CC0.

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