Changes in the genes expression involved in the ovarian function, induced by 3-methylcholanthrene, and its prevention by a-naphthoflavone

GALARZA, ROCÍO ALEJANDRA; RHON CALDERÓN, ERIC ALEJANDRO; FALETTI, ALICIA GRACIELA; LOMNICZI, ALEJANDRO

Sevilla

Congreso; 52nd Congress of the European Societies of Toxicology (EUROTOX); 2016

Sociedad Europea de Toxicología

3-Methylcholanthrene (3MC), a polyaromatic hydrocarbon, is an environmental pollutant that causes reproductive toxicity. Previous studies showed that 3MC alters the ovarian function by affecting the follicle integrity in rodents. We studied the effect of daily administration of 3MC on the gene expression involved in folliculogenesis, cell cycle and xenobiotic metabolism. Ovarian tissue from immature female rats, daily injected with 3MC (0.1?1 mg/kg) and/or α-naphthoflavone (αNF, 80 mg/kg) for 20 days, were used. Both doses of 3MC increased the mRNA expression of Akt1, Cdk2, Dnajb6, Igf2, Calr, Hspa8, Icam1, Ddr2, Dll1, Hes1, Notch2, Jag1, Cyp1a1, Cyp1b1, Ddx5, Foxn3 and Sp1 (p < 0.001); decrease the expression of Esr1, Cd9 and Itgb8 (p < 0.001); and showed no changes in Foxo3, Gdf9, Bmp15 and Itga4; all compared with controls. To assess whether the aryl hydrocarbon receptor (AhR) is involved in the 3MC-induced changes, chromatin immunoprecipitation assay was used. We found an increase of the promoters of Cyp1a1, Cyp1b1, Hes1, Jag1, Igf2, Dnajb6, Cdk2, Sp1 and Icam1, after AhR recruitment, compared with controls (p < 0.001). By studying trimethylation and acetylation of histone 3 from these genes, we found an increase in 6 and 7 compared with controls (p < 0.001), respectively. All these changes were prevented by the daily treatment with αNF. In conclusion (i) a daily exposure of 3MC alters the expression of different genes involved in the ovarian function by acting on different transcriptional process; (ii) the 3MC action seems to be mediated by AhR; and (iii) αNF prevents the toxic effect of 3MC on the ovary.