Multiomics Analysis Revealed the Molecular Mechanism of miRNAs in Fluoride-Induced Hepatic Glucose and Lipid Metabolism Disorders

Abstract

Fluoride-induced liver injury seriously endangers human and animal health and animal food safety, but the underlying mechanism remains unclear. This study aims to explore the mechanism of miRNAs in fluoride-induced hepatic glycolipid metabolism disorders. C57 male mice were used to establish the fluorosis model ( 22.62 mg/L F − , 12 weeks). The results indicated that fluoride increased fluoride levels, impaired the structure and function, and disrupted the glycolipid metabolism in the liver. Furthermore, the sequencing results showed that fluoride exposure resulted in the differential expression of 35 miRNAs and 480 mRNAs, of which 23 miRNAs were related to glycolipid metabolism. miRNA−mRNA network analyses and RT-PCR revealed that miRNAs mediated fluoride-induced disturbances in the hepatic glycolipid metabolism. Its possible mechanism was to regulate the insulin pathway, PPAR pathway, and FOXO pathway, which in turn affected the bile secretion, the metabolic processes of glucose, the decomposition of lipids, and the synthesis of unsaturated fatty acids in the liver. This study provides a theoretical basis for miRNAs as diagnostic indicators and target drugs for the treatment of fluoride-induced liver injury.

The interaction between miRNAs and hazardous materials

“…Furthermore, fluoride has been demonstrated to affect expression of 35 miRNAs, particularly those associated with glycolipid metabolism in the liver. In fact, these miRNAs could mediate fluoride-induced disturbance in the glycolipid metabolism, possibly through affecting activity of insulin, PPAR, and FOXO pathways [ 111 ].…”

Expression of SDF-1/CXCR4 and related inflammatory factors in sodium fluoride-treated hepatocytes

“…Excessive intake of elemental fluoride, however, can cause damage to bones and other important organs in the body [15], such as the cardiovascular and hepatic systems and teeth [16][17][18][19]. According to epidemiological investigations and in vitro and in vivo experimental studies, fluorosis may cause a certain degree of damage to the liver, inducing hepatic glucose and lipid metabolic dysfunction, and at the cellular level, fluorosis can cause swelling of the endoplasmic reticulum and mitochondria, reduced nuclear volume, nuclear membrane wrinkling and other defects in hepatocytes [20,21]. Fluorosis was shown to increase the levels of inflammatory factors [22].…”

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“…Excessive intake of elemental fluoride, however, can cause damage to bones and other important organs in the body [15], such as the cardiovascular and hepatic systems and teeth [16][17][18][19]. According to epidemiological investigations and in vitro and in vivo experimental studies, fluorosis may cause a certain degree of damage to the liver, inducing hepatic glucose and lipid metabolic dysfunction, and at the cellular level, fluorosis can cause swelling of the endoplasmic reticulum and mitochondria, reduced nuclear volume, nuclear membrane wrinkling and other defects in hepatocytes [20,21]. Fluorosis was shown to increase the levels of inflammatory factors [22].…”