Benzo(a)pyrene Exposure Suppressed Osteogenic and Adipogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells and Was Associated with Senescence-like Response

Human exposure to benzo(a)pyrene [B(a)P] from contaminated environmental pollutants may induce cellular senescence. Mesenchymal stem cells (MSCs) are responsible for maintaining bone homeostasis, mineralization and integrity. Senescent MSCs may result from exogenous chemical exposure, leading to diminished osteogenic potential and increased bone loss. This study elucidated the toxicological effects of B(a)P exposure in human bone marrow-derived MSCs (BM-hMSCs) under induced osteogenic and adipogenic differentiation by in vitro testing and transcriptomic analyses. Cell viability assays following 1–20 µM of B(a)P showed no toxic effects after 24 to 72 h of exposure. Non-cytotoxic concentrations of B(a)P (1–20 µM) suppressed the differentiation of BM-hMSCs into osteogenic and adipogenic lineages over 7 to 21 days, as indicated by reduced phenotypic parameters and molecular expression of differentiation markers compared with differentiation-induced cells. B(a)P decreased osteoblastic proliferation of signaling Wnt/β-catenin, with increased AhR/AhRR expression, which is related to osteogenic damage. Furthermore, B(a)P increased the expression of senescence markers, includingintracellular β-galactosidase, p21 and the secretory markers IL-1β and IL-6, in osteogenic-differentiated BM-hMSCs. The transcriptomic profile of osteogenic-differentiated BM-hMSCs exposed to 10 µM of B(a)P for 21 days revealed upregulation of stress and inflammatory responses, along with downregulation of cell cycle regulation and genes associated with cellular integrity. RNA-seq profiles also revealed upregulation of senescence-associated markers. Collectively, B(a)P may impair their differentiation capacity and is associated with senescence induction, partly through AhR activation. This study highlights the implications for skeletal health risk of chronic exposure to environmental pollutants by detection of senescent-associated markers.