Early Gestational Exposure to Inhaled Ozone Impairs Maternal Uterine Artery and Cardiac Function
Marcus Garcia, Raul Salazar, Thomas Wilson, Selita Lucas, Guy Herbert, Tamara Young, Jessica Begay, Jesse L Denson, Katherine Zychowski, Ryan Ashley, Stephanie Byrum, Samuel Mackintosh, Barry E Bleske, Andrew K Ottens, Matthew J CampenToxicological Sciences2021
Exposure to air pollutants such as ozone (O3) is associated with adverse pregnancy outcomes, including higher incidence of gestational hypertension, preeclampsia and peripartum cardiomyopathy; however, the underlying mechanisms of this association remain unclear. We hypothesized that O3 exposures during early placental formation would lead to more adverse cardiovascular effects at term for exposed dams, as compared to late-term exposures. Pregnant Sprague-Dawley rats were exposed (4 h) to either filtered air (FA) or O3 (0.3 or 1.0 ppm) at either gestational day (GD)10 or GD20, with longitudinal functional assessments and molecular endpoints conducted at term. Exposure at GD10 led to placental transcriptional changes at term that were consistent with markers in human preeclampsia, including reduced mmp10 and increased cd36, fzd1, and col1a1. O3 exposure, at both early and late gestation, induced a significant increase in maternal circulating soluble FMS-like tyrosine kinase-1 (sFlt-1), a known driver of preeclampsia. Otherwise, exposure to 0.3 ppm O3 at GD10 led to several late-stage cardiovascular outcomes in dams that were not evident in GD20-exposed dams, including elevated uterine artery resistance index and reduced cardiac output and stroke volume. GD10 O3 exposure proteomic profile in maternal hearts characterized by a reduction in proteins with essential roles in metabolism and mitochondrial function, while phosphoproteomic changes were consistent with pathways involved in cardiomyopathic responses. Thus, the developing placenta is an indirect target of inhaled O3 and that systemic maternal cardiovascular abnormalities may be induced by O3 exposure at a specific window of gestation.