Gestational oxidative stress protects against adult obesity and insulin resistance

Abstract

Pregnancy complications such as preeclampsia cause increased fetal oxidative stress and fetal growth restriction, and associate with a higher incidence of adult metabolic syndrome. However, the pathophysiological contribution of oxidative stress per se is experimentally difficult to discern and has not been investigated. This study determined, if increased intrauterine oxidative stress (IUOx) affects adiposity, glucose and cholesterol metabolism in adult Ldlr−/−xSod2+/+ offspring from crossing male Ldlr−/−xSod2+/+ mice with Ldlr−/−xSod2 +/- dams (IUOx) or Ldlr−/−xSod2 +/- males with Ldlr−/−xSod2+/+ dams (control). At 12 weeks of age mice received Western diet for an additional 12 weeks. Adult male IUOx offspring displayed lower body weight and reduced adiposity associated with improved glucose tolerance compared to controls. Reduced weight gain in IUOx was conceivably due to increased energy dissipation in white adipose tissue conveyed by higher expression of Ucp1 and an accompanying decrease in DNA methylation in the Ucp1 enhancer region. Female offspring did not show comparable phenotypes. These results demonstrate that fetal oxidative stress protects against the obesogenic effects of Western diet in adulthood by programming energy dissipation in white adipose tissue at the level of Ucp1.

Paternal alcohol exposures program intergenerational hormetic effects on offspring fetoplacental growth

“…As hypoxia and oxidative stress stimulate growth and differentiation of the placenta ( Pringle et al, 2010 ), suppressing these protective pathways may explain the enhanced growth we observe. Further, early gestational exposures to transient oxidative stress induce a similar repertoire of metabolic outcomes as those we identified in the male offspring of alcohol-exposed sires ( Dimova et al, 2020 ). If our mouse studies directly translate to humans, gene-environment differences in oxidative stress responses may play an unappreciated role in the susceptibility to alcohol-induced teratogenesis and contribute to the wide variation in FASD phenotypes and prevalence observed in the clinics ( Schaefer and Deere, 2011 ; McCarthy and Eberhart, 2014 ).…”

Sulforaphane induced NRF2 activation in obese pregnancy attenuates developmental redox imbalance and improves early-life cardiovascular function in offspring

“…6 B). While these data may indeed suggest developmental global NRF2 loss per se is somewhat cardioprotective, potentially agreeing with reports that mild oxidative stress in pregnancy improves offspring metabolic outcomes [ 75 ], the fact that SFN treatment enhanced contractility to NA in female and impaired Ach-induced relaxation in male NRF2KO offspring suggests that SFNs cardiovascular protective actions are indeed NRF2 mediated. In adult models of diabetic cardiomyopathy and vascular dysfunction NRF2 deficiency is reported to exacerbate pathology whereas NRF2 activation attenuates this phenotype [ [32] , [69] , [76] ], agreeing in part with our findings.…”

Paternal epigenetic influences on placental health and their impacts on offspring development and disease

“…In worms, multiple reports can link transgenerational germline programming to early-life mitochondrial dysfunction and the epigenetic regulation of antioxidant pathways (Kishimoto et al, 2017;Zhang et al, 2021c). Significantly, similar pathways are also present in mammalian systems, and transient, intrauterine episodes of placental oxidative stress induce improvements in hepatic metabolism, priming of antioxidant pathways, and resistance to high-fat dietinduced obesity; a phenomenon broadly termed mitohormesis (Yun and Finkel, 2014;Cox et al, 2018;Dimova et al, 2020). Our data examining low-level paternal alcohol exposures also identify altered transcription of placental mitochondrial genes (Thomas et al, 2021;, and the male offspring of alcoholexposed sires exhibit resistance to the effects of a high-fat diet (Chang et al, 2019b).…”