Reconstruction of genetic regulatory networks in human Sertoli cells exposed to Tetrachlorodibenzo-p-dioxin (TCDD)

Author(s)

Mariana Antunes Ribeiro

• Document type: Doctoral Thesis
• Press: Botucatu. 2017-09-01.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências. Botucatu
• Defense date: 2017-07-28
• Advisor: Wellerson Rodrigo Scarano

Abstract

Male fertility and spermatogenesis are directly linked to the ability of Sertoli cells to produce factors associated with the development of germ cells. Sertoli cells express receptors for FSH and testosterone, and are the major regulators of spermatogenesis. Approximately 60-70% of male infertility cases are considered idiopathic, due to the molecular mechanisms involved in spermatogenesis are still unknown. Recent studies report that microRNAs (miRNAs) are capable of modulating spermatogenesis in testicular function and its altered expression may be involved in male infertility. miRNAs may play a role in response to xenobiotics that have all the adverse consequences for health. An important group of organic compounds that are potentially toxic are the dioxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Experimental models of exposure to TCDD in mice showed that its exposure causes low sperm count and delayed puberty. In this study, we analyzed the effect of TCDD on human Sertoli cells after a exposure of 72h in vitro at a dose of 10nM. Our results showed that the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase decreased their activity and confirmed the oxidative stress caused by TCDD in this cell type. 78 miRNAs showed altered expression with upregulation of 73 miRNAs and downregulation of 5 miRNAs compared to the control group. Regarding the gene expression profile, 51 genes showed deregulated, of which 46 genes with upregulation and downregulation of 5 genes. Three tRNAs were downregulated due to exposure to TCDD. Furthermore, 30 piRNAs proved deregulated, 17 piRNAs with upregulation and 13 with downregulation when comparing the groups. 7 different matrix families of transcription factor binding sites showed statistically significant expression in Sertoli cells after exposure to TCDD. Several pathways have been altered by the action of the toxic agent. Furthermore, our study showed a low number of similar genes among the most expressed among humans, rats and mice, which reflects the physiology of each species and alerts the caution when using animal models as substitutes for human exposure. (AU)

• FAPESP's process: 13/12154-2 - Overall micro-RNA expression profile in human Sertoli cells (HSEC) after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
• Grantee: Mariana Antunes Ribeiro
• Support Opportunities: Scholarships in Brazil - Doctorate