Abstract
Tributyltin (TBT) is known as an endocrine-disrupting chemical. This study investigated the effects and possible mechanisms of TBT exposure on inducing human articular chondrocyte senescence in vitro at the human-relevant concentrations of 0.01–0.5 μM and mouse articular cartilage aging in vivo at the doses of 5 and 25 μg/kg/day, which were 5 times lower than the established no observed adverse effect level (NOAEL) and equal to NOAEL, respectively. TBT significantly increased the senescence-associated β-galactosidase activity and the protein expression levels of senescence markers p16, p53, and p21 in chondrocytes. TBT induced the protein phosphorylation of both p38 and JNK mitogen-activated protein kinases in which the JNK signaling was a main pathway to be involved in TBT-induced chondrocyte senescence. The phosphorylation of both ataxia-telangiectasia mutated (ATM) and histone protein H2AX (termed γH2AX) was also significantly increased in TBT-treated chondrocytes. ATM inhibitor significantly inhibited the protein expression levels of γH2AX, phosphorylated p38, phosphorylated JNK, p16, p53, and p21. TBT significantly stimulated the mRNA expression of senescence-associated secretory phenotype (SASP)-related factors, including IL-1β, TGF-β, TNF-α, ICAM-1, CCL2, and MMP13, and the protein expression of GATA4 and phosphorylated NF-κB-p65 in chondrocytes. Furthermore, TBT by oral gavage for 4 weeks in mice significantly enhanced the articular cartilage aging and abrasion. The protein expression of phosphorylated p38, phosphorylated JNK, GATA4, and phosphorylated NF-κB-p65, and the mRNA expression of SASP-related factors were enhanced in the mouse cartilages. These results suggest that TBT exposure can trigger human chondrocyte senescence in vitro and accelerating mouse articular cartilage aging in vivo.
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Acknowledgements
This study was supported in part by grant from Ministry of Science and Technology of Taiwan (MOST105-2314-B-002-009-MY3).
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Ministry of Science and Technology, Taiwan, (Grant no. MOST105-2314-B-002-009-MY3).
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Y-PC: methodology, formal analysis, writing—original draft. T-IW: methodology, visualization. D-CC: data curation, funding acquisition. R-SY: conceptualization, visualization, funding acquisition, writing—review and editing. S-HL: conceptualization, methodology, supervision, writing—review and editing.
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Chung, YP., Weng, TI., Chan, DC. et al. Low-dose tributyltin triggers human chondrocyte senescence and mouse articular cartilage aging. Arch Toxicol 97, 547–559 (2023). https://doi.org/10.1007/s00204-022-03407-x
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DOI: https://doi.org/10.1007/s00204-022-03407-x