Intergenerational effects of maternal obesity on offspring mitochondrial reactive oxygen species production and DNA damage

Abstract

Epidemiological studies have shown that offspring from pregnancies complicated by maternal obesity have a 4-fold greater risk for developing childhood obesity and symptoms of metabolic syndrome. The developmental origins of health and disease (DOHaD) hypothesis states that certain environmental exposures during critical windows of development may have consequences for an individuals long term health. DOHaD may explain a portion of the continual increase in obesity rates among children. In a non-human primate model, offspring of obese dams become sensitized to obesity-induced metabolic disruptions, including insulin resistance and mitochondrial disfunction. Increased reactive oxygen species (ROS) production contributes to mitochondrial defects observed in obesity. Oxidative stress, which is caused by overproduction of ROS, can lead to mitochondrial DNA (mtDNA) mutations, decreased copy number, reduced membrane permeability and subsequent suppression of mitochondrial respiratory chain activity. Therefore, I hypothesize that maternal obesity increases offspring mitochondrial ROS production leading to mtDNA damage without loss of mtDNA abundance. To study the effect of maternal obesity, we used a previously established Japanese macaque model of fetal programming. Dams were fed either a control (CON) diet or western style diet (WSD) prior to and during pregnancy and lactation. Offspring were then weaned at 8 months and fed a healthy CON diet. Skeletal muscle biopsies from offspring were collected at 3 years of age and relative mtDNA abundance was measured using quantitative PCR (qPCR) amplification of short regions of mtDNA. No differences were measured in the amount of mtDNA between offspring groups. Moving forward, I will test for elevations in ROS-induced mtDNA damage by qPCR amplification. Overall, these data indicate that exposure to maternal obesity and WSD during fetal development does not reduce mitochondrial abundance in skeletal muscle of adolescent offspring. Further tests are needed to determine whether observed reductions in mitochondrial homeostasis are linked to elevated ROS production.