Maternal liver lipid dysregulation mediates fetal developmental impairments induced by gestational co-exposure to ozone and heat in C57BL/6J Mice

Global warming has increased the frequency of simultaneous ozone and heat exposure, raising significant public health concerns. This study investigates the impacts of gestational exposure to ozone (1 ppm) and heat (34°C) under real-world conditions on fetal and placental development in C57BL/6 J mice, with a particular focus on the role of maternal hepatic lipid metabolism. Pregnant mice were exposed from gestational day (GD) 0 to GD17. Co-exposure to ozone and heat significantly reduced fetal birth weight and crown-rump length, and exacerbated adverse pregnancy outcomes, while exposure to ozone or heat alone did not significantly reduce fetal birth weight or crown-rump length. Placental development was impaired in the co-exposure group, particularly in the trophoblast zone. Ex vivo cell experiments revealed that plasma from co-exposed pregnant mice induced functional impairment in HTR-8/SVneo trophoblast cells. Maternal plasma analysis revealed a strong association between impaired placental and fetal development and abnormal lipid levels, which play a key role in causing developmental toxicity. Transcriptomic analysis of maternal liver tissue revealed that ozone exposure suppressed LDL and VLDL absorption, while heat promoted triglyceride synthesis. Co-exposure further exacerbated disruptions in hepatic lipid homeostasis. These findings highlight the detrimental effects of ozone and heat co-exposure on maternal and fetal health, suggesting that fetal impairments may be mediated by maternal hepatic lipid metabolism dysregulation.