Ozone-induced fetal growth restriction in rats is associated with sexually dimorphic placental and fetal metabolic adaptation

Abstract

Objective The importance of the placenta in mediating the pre- and post-natal consequences of fetal growth restriction has been increasingly recognized. However, the influence of placental sexual dimorphism on driving these outcomes has received little attention. The purpose of this study was to characterize how sex contributes to the relationship between placental metabolism and fetal programming utilizing a novel rodent model of growth restriction. Methods Fetal growth restriction was induced by maternal inhalation of 0.8 ppm ozone (4 h/day) during implantation receptivity (gestation days [GDs] 5 and 6) in Long-Evans rats. Control rats were exposed to filtered air. At GD 21, placental and fetal tissues were obtained for metabolic and genomic assessments. Results Growth-restricted male placentae exhibited increased mitochondrial biogenesis, increased oxygen consumption, and reduced nutrient storage. Male growth-restricted fetuses also had evidence of reduced adiposity and downregulation of hepatic metabolic signaling. In contrast, placentae from growth-restricted females had elevated markers of autophagy accompanied by an observed protection against hepatic metabolic perturbations. Despite this, growth restriction in females induced a greater number of hypothalamic gene and pathway alterations compared to growth-restricted males. Conclusions Increases in mitochondrial metabolism in growth-restricted male placentae likely initiates a sequela of adaptations that promote poor nutrient availability and adiposity. Divergently, the female placenta expresses protective mechanisms that may serve to increase nutrient availability to support fetal metabolic development. Collectively, this work emphasizes the importance of sex in mediating alterations in placental metabolism and fetal programming.

Latent, sex-specific metabolic health effects in CD-1 mouse offspring exposed to PFOA or HFPO-DA (GenX) during gestation

“…Prenatal exposure to BPA in CD-1 mice induced increased weight gain, reduced glucose tolerance, increased abdominal fat mass, and increased insulin levels in male offspring [ 71 ]. Recent work evaluating the effect of ozone exposure during gestation on offspring in rats found that programming of metabolic pathways in the fetal liver is impaired in males, but not females [ 72 ]. Increased sensitivity in males compared to females has also been well documented in toxicology studies [ 73 – 75 ].…”

Wildfire Smoke Exposure during Pregnancy: A Review of Potential Mechanisms of Placental Toxicity, Impact on Obstetric Outcomes, and Strategies to Reduce Exposure

“…Studies of non-pregnant individuals on the inhalation in urban settings of ambient particles and ozone for 2 h led to arterial vasoconstriction in healthy adults [ 106 ]. Ozone exposure during implantation appears to induce fetal growth restriction due to decreased uterine blood flow and is used to generate models of fetal growth restriction in pregnant Long-Evans rats [ 107 ]. Acute systemic inflammation and oxidative stress following PM exposure, as described above, are likely responsible for triggering endothelial dysfunction leading to vasoconstriction [ 56 , 82 , 108 ].…”

Sexually Dimorphic Accumulation of Persistent Organic Pollutants in Fetuses

“…When the intrauterine environment is disturbed in rodents and humans, placentas with male fetuses consume more energy to accelerate its own growth as well as the fetus’, accelerating epigenetic aging at the expense of adaptability and plasticity ( Tekola-Ayele et al, 2019 ; Yu et al, 2021 ). In contrast, placentas with female fetuses respond to disturbances with protective mechanisms such as slowing down growth and metabolism to ensure fetal survival ( Miller et al, 2020 ; Phuthong et al, 2020 ; Saoi et al, 2020 ; Weinheimer et al, 2020 ). These different growth strategies in response to disturbances may place male fetuses at a greater risk when exposed to POPs or other disturbing pollutants.…”