Impact of PFOS Exposure on Murine Fetal Hematopoietic Stem Cells, Associated with Intrauterine Metabolic Perturbation

In this study, we hypothesized that in-utero PFOS exposure disrupts maternal-fetal metabolism, affecting fetal liver hematopoietic stem cell (FL-HSC) development. Pregnant mice received PFOS (0.3 and 3 ug/g bw) and were sacrificed on gestation day 14.5. A significant increase in the liver/body weight ratio was observed at the high dose of PFOS exposure (H-PFOS). Metabolomic analysis of maternal blood plasma revealed notable disruptions in the metabolism of steroid hormones, purines, carbohydrates, and amino acids. The changes were reflected in the most enriched pathways of the amniotic fluid (AF) metabolome. A highly enriched tryptophan metabolism in AF significantly contributes to various immunological processes during pregnancy. Similarly, the metabolomic analysis of FL showed increased purine metabolism and disruptions in glucose and amino acid metabolism, especially at H-PFOS. Notably, FL exhibited significantly higher levels of polyunsaturated fatty acids, glycolytic and TCA metabolites, and a pro-inflammatory cytokine IL-23, which is essential for regulating hematopoiesis. The AF and FL data indicated that PFOS disrupted the intrauterine metabolic and inflammatory environment.Transcriptomic analysis of FL hematopoietic stem cells (HSCs) demonstrated disturbances in the PPAR signaling pathway, pyruvate metabolism, oxidative phosphorylation, and amino acid metabolism that correlate with FL metabolic alterations. Metabolomic analysis of FL-HSCs showed significant increases in glycerophospholipid and vitamin B6 metabolism associated with the regulation of HSC expansion and differentiation. Flow cytometric analysis confirmed an increase in HSC populations and activation of progenitors for megakaryocyte, erythrocyte, and lymphocyte lineage. The CFU assay showed a significant increase in BFU-E and CFU-G, while there was a decrease in CFU-GM in FL-HSCs from the H-PFOS group, indicating altered differentiation potential. These findings offer valuable insights into how PFOS exposure affects maternal-fetal metabolism and HSC developmental pathways in FL, emphasizing significant implications for pollution-perturbed immune functions. Our data reveals for the first time that in-utero PFOS exposure impacts fetal hematopoiesis.