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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.

SUBMITTER: Kunovac A

PROVIDER: S-EPMC8363568 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNano-titanium dioxide (nano-TiO2) is amongst the most widely utilized engineered nanomaterials (ENMs). However, little is known regarding the consequences maternal ENM inhalation exposure has on growing progeny during gestation. ENM inhalation exposure has been reported to decrease mitochondrial bioenergetics and cardiac function, though the mechanisms responsible are poorly understood. Reactive oxygen species (ROS) are increased as a result of ENM inhalation exposure, but it is unclear whether they impact fetal reprogramming. The purpose of this study was to determine whether maternal ENM inhalation exposure influences progeny cardiac development and epigenomic remodeling.ResultsPregnant FVB dams were exposed to nano-TiO2 aerosols with a mass concentration of 12.09 ± 0.26 mg/m3 starting at gestational day five (GD 5), for 6 h over 6 non-consecutive days. Aerosol size distribution measurements indicated an aerodynamic count median diameter (CMD) of 156 nm with a geometric standard deviation (GSD) of 1.70. Echocardiographic imaging was used to assess cardiac function in maternal, fetal (GD 15), and young adult (11 weeks) animals. Electron transport chain (ETC) complex activities, mitochondrial size, complexity, and respiration were evaluated, along with 5-methylcytosine, Dnmt1 protein expression, and Hif1α activity. Cardiac functional analyses revealed a 43% increase in left ventricular mass and 25% decrease in cardiac output (fetal), with an 18% decrease in fractional shortening (young adult). In fetal pups, hydrogen peroxide (H2O2) levels were significantly increased (~ 10 fold) with a subsequent decrease in expression of the antioxidant enzyme, phospholipid hydroperoxide glutathione peroxidase (GPx4). ETC complex activity IV was decreased by 68 and 46% in fetal and young adult cardiac mitochondria, respectively. DNA methylation was significantly increased in fetal pups following exposure, along with increased Hif1α activity and Dnmt1 protein expression. Mitochondrial ultrastructure, including increased size, was observed at both fetal and young adult stages following maternal exposure.ConclusionsMaternal inhalation exposure to nano-TiO2 results in adverse effects on cardiac function that are associated with increased H2O2 levels and dysregulation of the Hif1α/Dnmt1 regulatory axis in fetal offspring. Our findings suggest a distinct interplay between ROS and epigenetic remodeling that leads to sustained cardiac contractile dysfunction in growing and young adult offspring following maternal ENM inhalation exposure.

Project description:Currently, approximately 8 million adult Americans use electronic cigarettes (e-cigs) daily, including women of childbearing age. It is known that more than 10% of women smoke during their pregnancy, and recent surveys show that rates of maternal vaping are similar to rates of maternal cigarette smoking. However, the effects of inhaling e-cig aerosol on the health of fetuses remain unknown. The objective of the present study was to increase our understanding of the molecular effects caused by in utero exposures to e-cig aerosols on developing mouse lungs and, later in life, on the offspring's susceptibility to developing asthma.MethodsPregnant mice were exposed throughout gestation to either filtered air or vanilla-flavored e-cig aerosols containing 18 mg/mL of nicotine. Male and female exposed mouse offspring were sacrificed at birth, and then the lung transcriptome was evaluated. Additionally, once sub-groups of male offspring mice reached 4 weeks of age, they were challenged with house dust mites (HDMs) for 3 weeks to assess asthmatic responses.ResultsThe lung transcriptomic responses of the mouse offspring at birth showed that in utero vanilla-flavored e-cig aerosol exposure significantly regulated 88 genes in males (62 genes were up-regulated and 26 genes were down-regulated), and 65 genes were significantly regulated in females (17 genes were up-regulated and 48 genes were down-regulated). Gene network analyses revealed that in utero e-cig aerosol exposure affected canonical pathways associated with CD28 signaling in T helper cells, the role of NFAT in the regulation of immune responses, and phospholipase C signaling in males, whereas the dysregulated genes in the female offspring were associated with NRF2-mediated oxidative stress responses. Moreover, we found that in utero exposures to vanilla-flavored e-cig aerosol exacerbated HDM-induced asthma in 7-week-old male mouse offspring compared to respective in utero air + HDM controls.ConclusionsOverall, these data demonstrate that in utero e-cig aerosol exposure alters the developing mouse lung transcriptome at birth in a sex-specific manner and provide evidence that the inhalation of e-cig aerosols is detrimental to the respiratory health of offspring by increasing the offspring' susceptibility to developing lung diseases later in life.

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

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