Effects of Perinatal Exposure to Dibutyltin Chloride on Fat and Glucose Metabolism in Mice, and Molecular Mechanisms, in Vitro.
Effects of Perinatal Exposure to Dibutyltin Chloride on Fat and Glucose Metabolism in Mice, and Molecular Mechanisms, in Vitro.
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DOI：
10.1289/ehp3030
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发表时间：
2018-05
影响因子：
10.4
通讯作者：
Blumberg B
中科院分区：
文献类型：
--
作者：
Chamorro-García R;Shoucri BM;Willner S;Käch H;Janesick A;Blumberg B
有机锡二丁基锡（DBT）用于聚氯乙烯（PVC）塑料的制造，建筑材料和医疗器械。以前的动物研究表明，相对高剂量的DBT在子宫内发育期间具有有害影响，但对环境相关剂量的DBT暴露对肥胖和代谢疾病等终点的影响知之甚少。我们使用体外和体内模型测试了DBT的潜在致肥胖作用。我们使用人和小鼠多能间充质基质干细胞（MSCs）评估DBT对核受体活化和成脂潜能的影响。我们还评估了围产期暴露于环境相关剂量的DBT在C57 BL/6 J小鼠的影响。DBT激活人和小鼠，并在瞬时转染试验中，增加成脂基因的表达，促进成脂分化，并增加小鼠和人MSC中的脂质积累。DBT诱导的脂肪形成分化被拮抗剂T0070907消除，表明DBT主要通过。围产期暴露于低剂量的DBT导致增加脂肪储存，降低葡萄糖耐量，并增加循环瘦素水平的男性，但不是女性，小鼠。DBT通过一种途径诱导人和小鼠MSC中的脂质积聚，从而起到致肥剂的作用。在围产期发育过程中，体内暴露于生物学相关剂量的DBT导致小鼠脂肪储存增加、血浆瘦素水平升高和葡萄糖耐受不良。基于这些发现，我们认为，监测人体样本中的DBT水平可能有助于了解和潜在地预防人群中代谢紊乱率的上升。https://doi.org/10.1289/EHP3030
The organotin dibutyltin (DBT) is used in the manufacture of polyvinyl chloride (PVC) plastics, in construction materials, and in medical devices. Previous animal studies showed detrimental effects of DBT during in utero development at relatively high doses, but little was known about the effects of DBT exposure at environmentally relevant doses on endpoints such as obesity and metabolic disease. We tested the potential obesogenic effects of DBT using in vitro and in vivo models. We evaluated the effects of DBT on nuclear receptor activation and adipogenic potential using human and mouse multipotent mesenchymal stromal stem cells (MSCs). We also evaluated the effects of perinatal exposure to environmentally relevant doses of DBT in C57BL/6J mice. DBT activated human and mouse and in transient transfection assays, increased expression of adipogenic genes, promoted adipogenic differentiation and increased lipid accumulation in mouse and human MSCs, in vitro. DBT-induced adipogenic differentiation was abolished by the antagonist T0070907, indicating that DBT was acting primarily through . Perinatal exposure to low doses of DBT led to increased fat storage, decreased glucose tolerance, and increased circulating leptin levels in male, but not female, mice. DBT acted as an obesogen by inducing lipid accumulation in human and mouse MSCs through a pathway. In vivo exposure to biologically relevant doses of DBT during perinatal development led to increased fat storage, elevated leptin levels in plasma, and glucose intolerance in mice. Based on these findings, we posit that monitoring of DBT levels in human samples may aid in understanding and potentially preventing the rising rates of metabolic disorders in human populations. https://doi.org/10.1289/EHP3030