Sex differences in the development of pulmonary fibrosis in mouse offspring following prenatal diisononyl phthalate exposure

Abstract As a widely used plasticizer, Diisononyl phthalate (DINP) has been considered an emerging environmental pollutant. Epidemiological evidence shows that prenatal DINP exposure is linked to an increased risk of lung diseases in offspring and adults. However, little is known about their relationship at the molecular level. We exposed pregnant mice to DINP (100 mg/kg bw) by intragastric administration (once every two days) throughout gestation. On postnatal days (PNDs) 21 and 42 offspring were sacrificed and the lungs were collected. We found that prenatal DINP exposure significantly caused hypoalveolarization on PND 21 in male offspring, which was reversed during postnatal development. Moreover, prenatal DINP exposure significantly caused pulmonary fibrosis on PND 42 in male offspring. However, neither of these changes were observed in female offspring. KEGG enrichment showed that differentially expressed genes (DEGs) in the lungs of male offspring were closely associated with the calcium signaling and IL-17 signaling pathways. Importantly, decreased Htr4 expression might contribute to hypoalveolarization, and the elevated Il-17a expression might be responsible for sex-dependent differences in prenatal DINP exposure-induced pulmonary fibrosis.