Polybrominated diphenyl ether congener 99 (PBDE 99) promotes adipocyte lineage commitment of C3H10T1/2 mesenchymal stem cells

Abstract

Obesogens are defined as chemicals that trigger obesity partially by stimulating adipogenesis. Adipogenesis consists of two successive processes: the adipocyte lineage commitment of pluripotent stem cells and the differentiation of preadipocytes. Compared with the differentiation of preadipocytes, the effects of most environmental obesogens on adipocyte lineage commitment remain largely unknown. In this study, investigations are performed to explore the influences of PBDE 99 on the adipocyte lineage commitment based on C3H10T1/2, which has been widely used as a mesenchymal stem cell (MSC) model. Our results indicated that exposure to PBDE 99 during commitment stage resulted in significant up-regulation of subsequent adipogenesis in C3H10T1/2 MSCs. Interestingly, PBDE 99 did not affect the osteogenesis of C3H10T1/2 MSCs, although the adipogenesis and osteogenesis of MSCs are typically reciprocal. PBDE 99 was further demonstrated to significantly decrease the expression of Pref1, the marker of very early adipose mesenchymal precursor, and its downstream effector, Sox9. This result strongly suggested that PBDE 99 facilitated adipocyte commitment to exert adipogenic effect on C3H10T1/2 MSCs. Mechanistic studies revealed that PBDE 99 efficiently inhibited Hedgehog signaling transduction, a conserved negative regulator of the adipocyte lineage commitment. Furthermore, the effects of PBDE 99 on adipogenesis were abrogated by the co-treatment with SAG, a specific Hedgehog signaling activator, suggesting inhibition of Hedgehog signaling is responsible for the effect of PBDE 99 on adipocyte commitment. Taking together, these results strongly suggested enhanced adipocyte lineage commitment was involved in potential obesogenic effect of PBDE 99, presumably through repressing Hedgehog signalling during commitment stage. Moreover, the results of this study indicated that C3H10T1/2 can be used as a feasible MSCs cell model to evaluate the capabilities of potential obesogens on adipocyte commitment.