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Articles

Enhanced antioxidant capacity prevents epitranscriptomic and cardiac alterations in adult offspring gestationally-exposed to ENM

, , , , , , , & show all
Pages 812-831 | Received 19 Oct 2020, Accepted 18 Apr 2021, Published online: 08 May 2021
 

Abstract

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 (TiO2) inhalation exposure. Wild-type (WT) and mPHGPx (Tg) dams were exposed to nano-TiO2 aerosols with a mass concentration of 12.01 ± 0.50 mg/m3 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 N6-methyladenosine (m6A) content were assessed in adult progeny. MPHGPx enzymatic function was further evaluated in adult progeny and m6A-RNA immunoprecipitation (RIP) was combined with RT-qPCR to evaluate m6A 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. M6A-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 m6A 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.

Acknowledgements

We would like to thank Sherri A. Friend and the National Institute for Occupational Safety and Health, Morgantown, WV, USA for contributing in the physicochemical characterization of the nano-TiO2 aerosolized particles.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by The National Heart, Lung, and Blood Institute (NHLBI) under Grant [R01 HL-128485] (JMH), the National Institute of Environmental Health Sciences (NIEHS) under Grant [R01 ES-015022] (TRN), American Heart Association under Grant [AHA-20PRE35080170] (AK), American Heart Association under Grant [AHA-17PRE33660333] (QAH), National Institute on Aging (NIA) under Grant [5 T32 AG 52375-3] (KLG), WVU Genomics Core Facility support by CTSI Grant from the National Institute of General Medical Sciences (NIGMS) [U54GM104942], WVU Animal Models & Imaging Facility supported by the WVU Cancer Institute and NIH grants [P20 RR016440] and [P30 RR032138/GM103488], and the Community Foundation for the Ohio Valley Whipkey Trust (JMH).

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