VALPROIC ACID AS A REFERENCE SUBSTANCE FOR THE STUDY OF THE MOLECULAR-GENETIC MECHANISM OF OBESOGENITY OF ENDOCRINE DISRUPTERS

Abstract

Perfluorooctanoic acid (PFOA) and its derivatives are recognized as obesogens. Clinically used valproic acid (VPA) as a drug is structurally similar to PFOA. The objective of the investigation was to study the molecular-genetic mechanism of the weight gain by patients taking the VPA drugs and correlation with candidate genes involved in the metabolism of medium chain fatty acids. Weight and basal insulin level were evaluated in 238 patients both before and after 12 months of VPA treatment. Genotyping of SNPs rs1801282, C>G (Pro12Ala) gene PPARγ and rs1799883, G>A (Ala54Thr) gene FABP2 were performed with TaqMan Real-Time PCR Assay. Women who gained weight were genotyped «СС» for the rs1801282 PPARγ gene and appeared to have significantly higher insulin level (26.3±1.7 uU/ml) as compared to women with the same genotype and without weight gain (14.9±3.1 uU/ml). Similarly, men who gained weight and were genotyped «СС» for the rs1801282 PPARγ gene, showed significantly higher insulin level (25.4±1.8 uU/ml) as compared to men with the same genotype and without weight gain (13.,3±2.9 uU/ml). Women who gained weight and were genotyped «AA» or «AG» for the rs1799883 FABP2 gene had significantly higher insulin level (32.1±1.7 uU/ml) as compared to women with the same genotype and without weight gain (17.1±3.2 uU/ml). No correlation of insulin levels with weight gain and genotypes were identified for men. Obesogens, structurally similar to the medium chain fatty acids (in particular PFOA and analogues), can affect weight gain through the development of insulin resistance.