Maternal dibutyl benzene-1,2-dicarboxylate exposure accelerates bone marrow mesenchymal stem cells senescence to induce skeletal retardation in male offspring mice

Dibutyl benzene-1,2-dicarboxylate (DBP), a ubiquitous plasticizer, readily crosses the placenta, posing a risk to male offspring development. Previous studies have found that maternal DBP exposure leads to multiple organ development disorders in male offspring, but the effect on skeletal development in male offspring mice is unclear. In this study, pregnant mice were orally administered corn oil from day 12 of pregnancy or given different doses of DBP by gavage. Our results showed that prenatal DBP exposure induced dose-dependent deterioration in the male offspring's femoral bone microarchitecture, as revealed by micro-CT. In vitro, we found that the primary metabolite MBP disrupted the osteogenic-adipogenic balance in bone marrow mesenchymal stem cells (BMSCs) by suppressing osteogenic differentiation while promoting adipogenic differentiation. Mechanistically, MBP treatment induced a premature senescent phenotype in BMSCs, as evidenced by heightened senescence-associated β-galactosidase (SA-β-Gal) activity, upregulation of senescence markers (γH2AX, p16, p21), and increased secretion of senescence-associated inflammatory factors. Critically, treatment with rapamycin prevented MBP-induced senescence and restored the osteogenic-adipogenic balance in BMSCs. This study identifies BMSCs senescence as a pivotal mechanism underlying DBP-induced skeletal retardation, providing novel insights into the environmental bone toxicity of phthalate exposure.

Adipogenesis; Bone marrow mesenchymal stem cells; Dibutyl phthalate; Osteogenesis; Senescence.