Sex-dependent effects of developmental hypoxia on cardiac mitochondria from adult murine offspring

Hellgren, Kim T.; Premanandhan, Hajani; Quinn, Callum J.; Trafford, Andrew W.; Galli, Gina L. J.

doi:10.1016/j.freeradbiomed.2020.11.004

Cited by 24 publications

(37 citation statements)

References 74 publications

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“…dysfunction and metabolic disease, altered cardiac function, and increased susceptibility to ischemia-reperfusion injury [12][13][14]. These results are consistent with the fetal origins of adult disease (FOAD) theory proposed by David Barker [15].…”

Section: Introductionsupporting

confidence: 83%

Hypo-Hydroxymethylation of Nobox is Associated with Ovarian Dysfunction in Rat Offspring Exposed to Prenatal Hypoxia

Yao

et al. 2022

Reprod. Sci.

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Prenatal hypoxia (PH) is a common feature of a suboptimal intrauterine environment affecting the development of fetuses. Whether PH leads to abnormal ovary development is not yet clear. This study investigated ovarian function in offspring exposed to PH and the potential underlying molecular mechanisms. SD female rats (n = 12 per group) at 9 weeks of age were housed in individual cages (21% O2). After the pregnant rats were exposed to hypoxia (10.5% oxygen) from embryonic day (E) 5 to E21, PH offspring were generated. All animals maintained normoxia during lactation. The number of follicles was counted in female offspring at 3 months under an optical microscope. The expression of Nobox, Gdf9, and Tets was detected by quantitative real-time polymerase chain reaction (PCR) and Western blot. Global DNA hydroxymethylation was measured by dot blot. The hydroxymethylation level of the Nobox gene was evaluated with an NGS-based multiple targeted CpG hydroxymethylation analysis method. Body weight and ovary weight were significantly decreased in the PH group compared with the control group. PH offspring have abnormal estrous cycle, decreased serum anti-Mullerian hormone (AMH), and increased serum follicle-stimulating hormone (FSH), and follicular atresia, which are consistent with the clinical manifestations in patients with ovarian dysfunction. In terms of mechanism, the expression of Nobox was significantly decreased in the PH group. Subsequent high-throughput sequencing results showed that the level of hydroxymethylation in the candidate region of the Nobox gene was reduced. Cultured cells treated with hypoxia exhibited lower levels of both 5hmC and Nobox, while vitamin C, a coactivator of Tets, rescued hypo-hydroxymethylation and increased the expression level of Nobox. This study indicated that PH could cause hypo-hydroxymethylation of Nobox through epigenetic regulation and may consequently contribute to ovarian dysfunction in adult rat offspring.

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Section: Introductionsupporting

confidence: 83%

Hypo-Hydroxymethylation of Nobox is Associated with Ovarian Dysfunction in Rat Offspring Exposed to Prenatal Hypoxia

Yao

et al. 2022

Reprod. Sci.

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“…( Thompson et al, 2018 ). Similar sex-based differences were seen in adult mice that had developed under hypoxic conditions ( Hellgren et al, 2021 ). Cardiomyocytes from juvenile snapping turtles incubated in hypoxia exhibited lower LEAK and OXPHOS mitochondrial oxygen fluxes than their normoxic counterparts ( Galli et al, 2021 ).…”

Section: Discussionsupporting

confidence: 58%

“…Developing under intrauterine growth restriction or low oxygen conditions produces deleterious effects on the cardiovascular system of developing amniotes ( Giussani et al, 2012 ; Giussani and Davidge, 2013 ; Louey and Thornburg, 2005 ). Exposure to chronic hypoxia during fetal development can produce negative cardiovascular effects at the fetal and neonatal stages ( Thompson et al, 2018 , 2020 ) and later into the juvenile and adult stages ( Giussani and Davidge, 2013 ; Hellgren et al, 2021 ). Hypoxia during prenatal development remodels cardiac tissue in fetal and neonatal rats ( Tong et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

“…Cardiac mitochondria from another archosaur, the American alligator, shows limited effects of incubating under hypoxic conditions ( Galli et al, 2016 ). Developing under hypoxia in mice and snapping turtles was found to alter mitochondrial function in the adult, but was not studied in the embryo or neonate ( Galli et al, 2021 ; Hellgren et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Developing chicken cardiac muscle mitochondria are resistant to variations in incubation oxygen levels

Starr

Dzialowski

2022

Current Research in Physiology

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“…The consequences of insults occurring at such stages usually appear after a period of latency, manifested spontaneously, or provoked by some other insults [ 16 ]. However, the question on the role of gestational age at the time of hypoxic exposure has not been extensively addressed in the literature [ 12 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Acute Prenatal Hypoxia in Rats Affects Physiology and Brain Metabolism in the Offspring, Dependent on Sex and Gestational Age

Граф

Maslova

Artiukhov

et al. 2022

IJMS

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Hypoxia is damaging to the fetus, but the developmental impact may vary, with underlying molecular mechanisms unclear. We demonstrate the dependence of physiological and biochemical effects of acute prenatal hypoxia (APH) on sex and gestational age. Compared to control rats, APH on the 10th day of pregnancy (APH-10) increases locomotion in both the male and female offspring, additionally increasing exploratory activity and decreasing anxiety in the males. Compared to APH-10, APH on the 20th day of pregnancy (APH-20) induces less behavioral perturbations. ECG is changed similarly in all offspring only by APH-10. Sexual dimorphism in the APH outcome on behavior is also observed in the brain acetylation system and 2-oxoglutarate dehydrogenase reaction, essential for neurotransmitter metabolism. In view of the perturbed behavior, more biochemical parameters in the brains are assessed after APH-20. Of the six enzymes, APH-20 significantly decreases the malic enzyme activity in both sexes. Among 24 amino acids and dipeptides, APH-20 increases the levels of only three amino acids (Phe, Thr, and Trp) in male offspring, and of seven amino acids (Glu, Gly, Phe, Trp, Ser, Thr, Asn) and carnosine in the female offspring. Thus, a higher reactivity of the brain metabolism to APH stabilizes the behavior. The behavior and brain biochemistry demonstrate sexually dimorphic responses to APH at both gestational stages, whereas the APH effects on ECG depend on gestational age rather than sex.

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Sex-dependent effects of developmental hypoxia on cardiac mitochondria from adult murine offspring

Cited by 24 publications

References 74 publications

Hypo-Hydroxymethylation of Nobox is Associated with Ovarian Dysfunction in Rat Offspring Exposed to Prenatal Hypoxia

Hypo-Hydroxymethylation of Nobox is Associated with Ovarian Dysfunction in Rat Offspring Exposed to Prenatal Hypoxia

Developing chicken cardiac muscle mitochondria are resistant to variations in incubation oxygen levels

Acute Prenatal Hypoxia in Rats Affects Physiology and Brain Metabolism in the Offspring, Dependent on Sex and Gestational Age

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