Low-expressional IGF1 mediated methimazole-induced liver developmental toxicity in fetal mice. (1st September 2018)

• Record Type: Journal Article
• Authors: Wang, Guihua; He, Bo; Hu, Wen; Liu, Kexin; Gong, Xiaohan; Kou, Hao; Guo, Yu; Wang, Hui
• Is Part Of: Toxicology. Volume 408(2018)
• Page Start: 70
• Page End: 79
• Publication Date: 2018-09-01
• Subjects: IGF-1R insulin-like growth factor-1 receptor -- Akt2 serine-threonine protein kinase 2 -- HMGCR HMG CoA reductase -- FASN fatty acid synthase -- PEPCK phosphoenolpyruvate carboxykinase -- PCNA proliferating cell Nuclear antigen -- HNF4α hepatocyte nuclear factor 4α -- ALB albumin -- AFP alpha fetoprotein -- GAPDH glyceraldehyde phosphate dehydrogenase -- Akt serine-threonine protein kinase -- p-Akt phosphorylated Akt -- ERK extracellular regulated protein kinase -- p-ERK phosphorylated ERK -- GD gestational day -- IGF1 insulin-like growth factor 1 -- IUGR intrauterine growth retardation -- PME prenatal methimazole exposure -- ATDs anti-thyroid drugs; Prenatal methimazole exposure -- Fetal liver developmental toxicity -- Insulin-like growth factor 1 (IGF1) -- Glucose and lipid metabolic function; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2018.07.004
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: Anti-thyroid drugs (ATDs) therapy is necessary for pregnant women with hyperthyroidism. However, there is a lack of studies on developmental toxicity of ATDs. In this study, we observed the developmental toxicity of fetal liver induced by prenatal methimazole exposure (PME) in mice, and explored the potential mechanism. Pregnant Kunming mice were administered intragastrically with 4.5 or 18 mg/kg·d methimazole from gestational day (GD) 9∼18. After PME, the birth weights of the offspring mice were decreased, and the liver morphology, development indexes and metabolic function were all altered in different degree in the PME fetuses. Meanwhile, PME decreased the levels of serum and hepatic insulin-like growth factor 1 (IGF1), and reduced the gene expression of IGF1 downstream signaling pathway. Furthermore, the protein levels of phosphorylated-extracellular regulated protein kinases (p-ERK) and serine-threonine protein kinase (p-Akt) were also reduced. Furthermore, methimazole disturb hepatocyte differentiation, maturation and metabolic function through suppressing IGF1 signaling pathway in HepG2 cells. These results demonstrated that PME could induce fetal liver developmental toxicity, and the underlying mechanism was related to low-expression of hepatic IGF1 caused by methimazole, which mediated abnormal liver morphology and metabolic function.