Developmentally Regulated CYP2E1 Expression Is Associated with a Fetal Pulmonary Transcriptional Response to Maternal Acetaminophen Exposure

<b>Background/Objectives</b>: Acetaminophen (APAP) is used during 50-60% of pregnancies in the U.S. and has been associated with childhood respiratory morbidity, though the underlying mechanism remains unclear. APAP-induced injury is dependent on cell-specific expression of CYP2E1, the enzyme that metabolizes APAP into the mitochondrial toxin NAPQI. In mice, pulmonary <i>Cyp2e1</i> expression peaks during the saccular stage of lung development on embryonic day 18 (E18). We investigated whether this developmental surge in <i>Cyp2e1</i> triggers a pulmonary transcriptional response to maternal APAP exposure in embryonic lungs. <b>Methods</b>: Pregnant dams were exposed to APAP on E17 or E18 (150 or 250 mg/kg, IP) using doses derived from prior studies. We assessed the induction of NRF2 target genes and genes associated with inflammation, apoptosis and cellular stress due to their roles in APAP-induced oxidative and cellular stress. <b>Results</b>: At E17, maternal treatment with APAP induced pulmonary <i>Cyp2e1</i> but resulted in inconsistent transcriptional changes. In contrast, maternal APAP at E18 triggered a robust transcriptional induction of <i>Cyp2e1</i>, NRF2 targets and markers of apoptosis, inflammation and cellular stress. Histopathology at birth after E18 APAP exposure revealed no acute pulmonary injury. <b>Conclusions</b>: We demonstrate a developmentally regulated, dose-dependent transcriptional response to maternal APAP in the embryonic murine lung. Importantly, transcriptional responses do not directly indicate lung injury; thus, future studies should assess protein-level changes following APAP exposure. This study underscores the need for further investigation into the role of developmentally regulated <i>Cyp2e1</i> expression in APAP-induced toxicity and long-term respiratory morbidity.