Citation:

Miller, C., A. Henriquez, E. Stewart, K. Lavrich, D. Freeborn, P. Kodavanti, G. Carswell, B. Chorley, U. Kodavanti, AND J. Dye. Peri-implantation ozone exposure induces sexually dimorphic placental-fetal-brain axis abnormalities. Society of Toxicology, Baltimore, MD, March 10 - 14, 2019.

Impact/Purpose:

Peri-implantation ozone exposure induces fetal growth restriction in the rat. However, the influence of placental health in mediating the impact of ozone on fetal size and neurodevelopment has not been studied. Therefore, we examined placental metabolic adaptations and alterations in neurodevelopment.

Description:

Peri-implantation ozone exposure induces fetal growth restriction in the rat. However, the influence of placental health in mediating the impact of ozone on fetal size and neurodevelopment has not been studied. Therefore, we examined placental metabolic adaptations and alterations in neurodevelopment. Utilizing fresh and frozen placental tissues collected at gestation day (GD) 21 from Long-Evans rats, we investigated placental metabolic endpoints including oxygen consumption and respiration, mitochondrial biogenesis, and changes in macronutrient concentrations and markers of autophagy. Fetal energy homeostasis was determined using body composition, hepatic triglycerides, and hypothalamic RNAseq. Results show that male placentas from ozone-exposed dams had increased mitochondrial respiration, ATP production, increased mitochondrial content, and reduced concentrations of triglycerides, cholesterol, and glucose. While female placentas failed to show these changes, they had evidence of AMPK phosphorylation and autophagy. Taken together, we next hypothesized that male and female fetuses would have sex-specific differences in body adiposity related to the aforementioned placental adaptations. Accordingly, male fetuses from ozone-exposed dams had reduced adiposity and hepatic triglyceride levels, whereas the female fetuses did not. Lastly, RNAseq within the hypothalamus of male fetuses revealed a reduction in ribosomal protein mRNA, a phenomenon that may be related to reduced amino acid availability for protein synthesis and diminished cellular growth. While the hypothalamus of female fetuses did not appear to be nutrient-starved, RNAseq analysis of the hypothalamus revealed significant reductions in serotonergic and dopaminergic genes. Furthermore, female hypothalami had reduced autophagic-related gene expression and increased ribosomal protein mRNAs. Together, we demonstrate that following peri-implantation ozone exposure, the placenta adapts in a sexually dimorphic manner. This adaptation may impact the nutrient availability of the fetus and disrupt neurodevelopment, rendering offspring sensitive to neurological deficits later in life. Abstract does not reflect US EPA policy.

Record Details: