Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Laksi, Bangkok, Thailand; Chulabhorn Graduate Institute, Laksi, Bangkok, Thailand.
Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Laksi, Bangkok, Thailand; Chulabhorn Graduate Institute, Laksi, Bangkok, Thailand; Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand.
Int J Hyg Environ Health. 2023 May;250:114124. doi: 10.1016/j.ijheh.2023.114124. Epub 2023 Mar 28.
The mechanisms underlying the association between prenatal arsenic exposure and the development of metabolic diseases remain unclear. Aberrant adipogenesis and adipokine production are associated with increased risk for the development of metabolic diseases in susceptible populations. Generation of mature adipocytes is tightly regulated by the expression of genes encoding: peroxisome proliferator-activated receptor γ (PPARG), fatty acid-binding protein (FABP4), and glucose transporter-4 (SLC2A4), and adipokines such as leptin (LEP) and adiponectin (ADIPOQ). This study aimed to investigate the expression of these genes, which are associated with the pathogenesis of metabolic diseases in newborns and children exposed to arsenic in utero. A high arsenic exposed group showed significantly decreased PPARG and FABP4 expression in cord blood samples from newborns and in saliva samples from children. By contrast, the expression of the SLC2A4 and ADIPOQ mRNA was significantly decreased in high-arsenic exposed children. Furthermore, the levels of toenail arsenic were negatively correlated with the salivary mRNA expression levels of PPARG (r = -0.412, p < 0.01), aP2 (r = -0.329, p < 0.05), and SLC2A4 (r = -0.528, p < 0.01). In vitro studies utilizing umbilical cord derived mesenchymal stem cells (UC-MSCs) as a surrogate for fetal MSCs showed that arsenite treatment (0.5 μM and 1 μM) significantly impaired adipogenic differentiation in a concentration dependent manner. Such impairment may be related to a significant decrease in the expression of: PPARγ, FABP4, and SLC2A4 observed at 1 μM arsenite. Arsenite treatment also promoted inflammation through a significant increase in the mRNA expression levels of the pro-inflammatory adipokine, LEP, and the inflammatory cytokines: CXCL6, IL-1β, and CXCL8. Collectively, our results suggests that such alterations may be a consequence of the effects of arsenic exposure on fetal MSCs eventually leading to impaired adipogenic differentiation and the promotion of inflammation, both of which contribute to the development of metabolic diseases later in life.
砷暴露与代谢性疾病发展之间的关联的潜在机制尚不清楚。异常的脂肪生成和脂肪因子产生与易感人群代谢性疾病发展的风险增加有关。成熟脂肪细胞的生成受到编码过氧化物酶体增殖物激活受体 γ (PPARG)、脂肪酸结合蛋白 4 (FABP4) 和葡萄糖转运蛋白 4 (SLC2A4) 的基因以及瘦素 (LEP) 和脂联素 (ADIPOQ) 等脂肪因子的表达调控。本研究旨在探讨这些基因在宫内砷暴露的新生儿和儿童中与代谢性疾病发病机制相关的表达。高砷暴露组显示新生儿脐带血样本和儿童唾液样本中 PPARG 和 FABP4 的表达显著降低。相比之下，高砷暴露组儿童的 SLC2A4 和 ADIPOQ mRNA 表达显著降低。此外，脚趾甲砷含量与唾液中 PPARG (r = -0.412，p < 0.01)、aP2 (r = -0.329，p < 0.05) 和 SLC2A4 (r = -0.528，p < 0.01) 的 mRNA 表达水平呈负相关。利用脐带来源的间充质干细胞 (UC-MSCs) 作为胎儿 MSC 的替代物进行的体外研究表明，亚砷酸盐处理 (0.5 μM 和 1 μM) 以浓度依赖的方式显著损害脂肪生成分化。这种损害可能与观察到的 1 μM 亚砷酸盐处理时 PPARγ、FABP4 和 SLC2A4 的表达显著下降有关。亚砷酸盐处理还通过促炎脂肪因子 LEP 和炎性细胞因子：CXCL6、IL-1β 和 CXCL8 的 mRNA 表达水平的显著增加促进了炎症。总的来说，我们的结果表明，这种改变可能是砷暴露对胎儿 MSC 影响的结果，最终导致脂肪生成分化受损和炎症的促进，这两者都有助于代谢性疾病在以后的生活中发展。
