PMID- 33969789 OWN - NLM STAT- MEDLINE DCOM- 20211125 LR - 20220325 IS - 1743-5404 (Electronic) IS - 1743-5390 (Print) IS - 1743-5390 (Linking) VI - 15 IP - 6 DP - 2021 Aug TI - Enhanced antioxidant capacity prevents epitranscriptomic and cardiac alterations in adult offspring gestationally-exposed to ENM. PG - 812-831 LID - 10.1080/17435390.2021.1921299 [doi] AB - Maternal engineered nanomaterial (ENM) exposure during gestation has been associated with negative long-term effects on cardiovascular health in progeny. Here, we evaluate an epitranscriptomic mechanism that contributes to these chronic ramifications and whether overexpression of mitochondrial phospholipid hydroperoxide glutathione peroxidase (mPHGPx) can preserve cardiovascular function and bioenergetics in offspring following gestational nano-titanium dioxide (TiO(2)) inhalation exposure. Wild-type (WT) and mPHGPx (Tg) dams were exposed to nano-TiO(2) aerosols with a mass concentration of 12.01 +/- 0.50 mg/m(3) starting from gestational day (GD) 5 for 360 mins/day for 6 nonconsecutive days over 8 days. Echocardiography was performed in pregnant dams, adult (11-week old) and fetal (GD 14) progeny. Mitochondrial function and global N(6)-methyladenosine (m(6)A) content were assessed in adult progeny. MPHGPx enzymatic function was further evaluated in adult progeny and m(6)A-RNA immunoprecipitation (RIP) was combined with RT-qPCR to evaluate m(6)A content in the 3'-UTR. Following gestational ENM exposure, global longitudinal strain (GLS) was 32% lower in WT adult offspring of WT dams, with preservation in WT offspring of Tg dams. MPHGPx activity was significantly reduced in WT offspring (29%) of WT ENM-exposed dams, but preserved in the progeny of Tg dams. M(6)A-RIP-qPCR for the SEC insertion sequence region of mPHGPx revealed hypermethylation in WT offspring from ENM-exposed WT dams, which was thwarted in the presence of the maternal transgene. Our findings implicate that m(6)A hypermethylation of mPHGPx may be culpable for diminished antioxidant capacity and resultant mitochondrial and cardiac deficits that persist into adulthood following gestational ENM inhalation exposure. FAU - Kunovac, Amina AU - Kunovac A AD - Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA. AD - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA. AD - Center for Inhalation Toxicology (iTOX), West Virginia University School of Medicine, Morgantown, WV, USA. FAU - Hathaway, Quincy A AU - Hathaway QA AD - Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA. AD - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA. AD - Center for Inhalation Toxicology (iTOX), West Virginia University School of Medicine, Morgantown, WV, USA. FAU - Pinti, Mark V AU - Pinti MV AD - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA. AD - West Virginia University School of Pharmacy, Morgantown, WV, USA. FAU - Durr, Andrya J AU - Durr AJ AD - Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA. AD - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA. FAU - Taylor, Andrew D AU - Taylor AD AD - Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA. AD - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA. FAU - Goldsmith, William T AU - Goldsmith WT AD - Center for Inhalation Toxicology (iTOX), West Virginia University School of Medicine, Morgantown, WV, USA. AD - Department of Physiology & Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA. FAU - Garner, Krista L AU - Garner KL AD - Center for Inhalation Toxicology (iTOX), West Virginia University School of Medicine, Morgantown, WV, USA. AD - Department of Physiology & Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA. FAU - Nurkiewicz, Timothy R AU - Nurkiewicz TR AD - Center for Inhalation Toxicology (iTOX), West Virginia University School of Medicine, Morgantown, WV, USA. AD - Department of Physiology & Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA. FAU - Hollander, John M AU - Hollander JM AD - Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA. AD - Mitochondria, Metabolism & Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA. AD - Center for Inhalation Toxicology (iTOX), West Virginia University School of Medicine, Morgantown, WV, USA. LA - eng GR - R56 HL128485/HL/NHLBI NIH HHS/United States GR - 17PRE33660333/AHA/American Heart Association-American Stroke Association/United States GR - P30 RR032138/RR/NCRR NIH HHS/United States GR - U54 GM104942/GM/NIGMS NIH HHS/United States GR - R01 ES015022/ES/NIEHS NIH HHS/United States GR - P30 GM103488/GM/NIGMS NIH HHS/United States GR - P20 RR016440/RR/NCRR NIH HHS/United States GR - R01 HL128485/HL/NHLBI NIH HHS/United States GR - P20 GM121322/GM/NIGMS NIH HHS/United States GR - T32 AG052375/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210508 PL - England TA - Nanotoxicology JT - Nanotoxicology JID - 101233132 RN - 0 (Antioxidants) SB - IM MH - Adult MH - Antioxidants MH - Female MH - Fetus MH - Heart MH - Humans MH - Maternal Exposure MH - *Nanostructures MH - Pregnancy MH - *Prenatal Exposure Delayed Effects PMC - PMC8363568 MID - NIHMS1721864 OTO - NOTNLM OT - Environmental exposure OT - GPx4 OT - M6A OT - N6-methyladenosine OT - mitochondria COIS- Disclosure statement No potential conflict of interest was reported by the author(s). EDAT- 2021/05/11 06:00 MHDA- 2021/11/26 06:00 PMCR- 2021/08/14 CRDT- 2021/05/10 09:16 PHST- 2021/05/11 06:00 [pubmed] PHST- 2021/11/26 06:00 [medline] PHST- 2021/05/10 09:16 [entrez] PHST- 2021/08/14 00:00 [pmc-release] AID - 10.1080/17435390.2021.1921299 [doi] PST - ppublish SO - Nanotoxicology. 2021 Aug;15(6):812-831. doi: 10.1080/17435390.2021.1921299. Epub 2021 May 8.