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

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.

Keywords:

• Environmental exposure
• GPx4
• mitochondria
• N6-methyladenosine
• M6A

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).