PFAS exposure is detrimental to placental function and fetal development by disrupting mitochondrial function and metabolism

About This Grant

Per- and poly-fluoroalkyl substances (PFAS) exposure is widespread and has sparked major concerns about health impacts in highly contaminated communities. The Feng lab has made significant contributions to our understanding of the reproductive toxicity of PFAS by studying PFAS mixtures that replicate PFAS levels in highly contaminated drinking water, as well as emerging PFAS compounds such as perfluorobutane sulfonic acid (PFBS). We have reported that maternal exposure to PFAS mixtures and PFBS at environmentally relevant doses leads to adverse birth outcomes through dysregulation of placental function and fetal neurodevelopment. Recently, our preliminary data demonstrated that exposure to a PFAS mixture or PFBS leads to oxygen accumulation in placentas and embryos during pregnancy and induces mitochondrial oxidative stress in both human placental trophoblast stem cells and murine fetal brains. In this proposal, we will thoroughly examine our hypothesis that PFAS exposure is detrimental to placental function and fetal development via disruption of mitochondrial activities and metabolism. Our specific aims are to: 1) Investigate mitochondrial perturbations associated with PFBS exposures in human placental trophoblast cells; 2) Determine which specific mitochondria- relevant syncytiotrophoblast functions are altered by PFBS exposure; and 3) Assess alterations in placental hemodynamics, oxygenation, and mitochondria-relevant metabolism by PFBS and PFAS mixtures in mice. Novelty: We will address the health impacts of PFAS mixtures that mimic highly contaminated community drinking water and specifically focus on an emerging PFAS compound, whereas most previous studies focused on single legacy compounds and used less clinically applicable exposure levels. In addition, unique, optimized, physiologically relevant human placental trophoblast stem cell-derived organoid models will be used to model the human maternal-fetal interface in vitro. Finally, an innovative, in vivo photoacoustic imaging system will be used to study placental hemodynamics in a mouse model longitudinally. This study will uncover potential druggable intervention targets (mitochondrial oxidative stress) that might mitigate the adverse effects of perinatal PFAS exposure. Furthermore, this study will advance our understanding of gender-specific health effects of perinatal PFAS exposure that will undoubtedly have implications for personalized diagnostics and therapeutic interventions. Feasibility: Combining expertise and preliminary studies provides a strong foundation for this proposal. Dr. Feng’s lab has established the perinatal PFAS exposure in vitro and in vivo models; this proposal is an extension of her previous projects. Dr. Schust's lab has extensive experience working with placental trophoblast-derived organoids and developed the novel properly polarized system used here. Dr. Yao’s lab has focused on developing novel photoacoustic technologies for assessing tissue hemodynamic parameters. Dr. Santos is an environmental toxicologist focusing on mitochondrial toxicants. Our study will significantly contribute to our understanding of the health impacts of PFAS and provide clues for intervention strategies.