PMID- 33146391 OWN - NLM STAT- MEDLINE DCOM- 20210818 LR - 20240314 IS - 1096-0929 (Electronic) IS - 1096-6080 (Print) IS - 1096-0929 (Linking) VI - 179 IP - 1 DP - 2021 Jan 6 TI - Early Gestational Exposure to Inhaled Ozone Impairs Maternal Uterine Artery and Cardiac Function. PG - 121-134 LID - 10.1093/toxsci/kfaa164 [doi] AB - 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 with 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, whereas phosphoproteomic changes were consistent with pathways involved in cardiomyopathic responses. Thus, the developing placenta is an indirect target of inhaled O3 and systemic maternal cardiovascular abnormalities may be induced by O3 exposure at a specific window of gestation. CI - (c) The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Garcia, Marcus AU - Garcia M AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. FAU - Salazar, Raul AU - Salazar R AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. FAU - Wilson, Thomas AU - Wilson T AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. FAU - Lucas, Selita AU - Lucas S AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. FAU - Herbert, Guy AU - Herbert G AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. FAU - Young, Tamara AU - Young T AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. FAU - Begay, Jessica AU - Begay J AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. FAU - Denson, Jesse L AU - Denson JL AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. FAU - Zychowski, Katherine AU - Zychowski K AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. FAU - Ashley, Ryan AU - Ashley R AD - Department of Animal and Range Sciences, New Mexico State University, Las Cruces, New Mexico 88003. FAU - Byrum, Stephanie AU - Byrum S AD - Arkansas Children's Research Institute, Little Rock, Arkansas 72202. FAU - Mackintosh, Samuel AU - Mackintosh S AD - Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205. FAU - Bleske, Barry E AU - Bleske BE AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. FAU - Ottens, Andrew K AU - Ottens AK AD - Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia 23298-0709. FAU - Campen, Matthew J AU - Campen MJ AD - Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. LA - eng GR - P20 GM103451/GM/NIGMS NIH HHS/United States GR - P20 GM130422/GM/NIGMS NIH HHS/United States GR - K99 ES029104/ES/NIEHS NIH HHS/United States GR - K12 GM088021/GM/NIGMS NIH HHS/United States GR - R00 ES029104/ES/NIEHS NIH HHS/United States GR - P20 GM121293/GM/NIGMS NIH HHS/United States GR - R01 ES014639/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Toxicol Sci JT - Toxicological sciences : an official journal of the Society of Toxicology JID - 9805461 RN - 66H7ZZK23N (Ozone) SB - IM MH - Animals MH - Female MH - Humans MH - *Ozone/toxicity MH - Placenta MH - Pregnancy MH - Proteomics MH - Rats MH - Rats, Sprague-Dawley MH - *Uterine Artery PMC - PMC8453811 OTO - NOTNLM OT - cardiomyopathy OT - cardiovascular OT - gestational hypertension OT - intrauterine OT - maternal OT - ozone OT - placenta OT - preeclampsia EDAT- 2020/11/05 06:00 MHDA- 2021/08/19 06:00 PMCR- 2020/11/04 CRDT- 2020/11/04 08:44 PHST- 2020/11/05 06:00 [pubmed] PHST- 2021/08/19 06:00 [medline] PHST- 2020/11/04 08:44 [entrez] PHST- 2020/11/04 00:00 [pmc-release] AID - 5955789 [pii] AID - kfaa164 [pii] AID - 10.1093/toxsci/kfaa164 [doi] PST - ppublish SO - Toxicol Sci. 2021 Jan 6;179(1):121-134. doi: 10.1093/toxsci/kfaa164.