Combined proteomic and miRNome analyses of mouse testis exposed to an endocrine disruptors chemicals mixture reveals altered toxicological pathways involved in male infertility

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The increase in male idiopathic infertility has been associated with daily exposure to endocrine disruptors chemicals (EDCs). Nevertheless, the mechanisms of action in relation to dysregulating proteins and regulatory microRNAs are unknown.We combined proteomic and miRNome analyses of mouse testis chronically exposed to low doses of a define mixture of EDCs [phthalates: bis (2-ethylhexyl), dibutyl and benzyl-butyl; 4-nonylphenol and 4-tert-octylphenol], administered in the drinking water from conception until adulthood (post-natal day 60/75) and compared them with no-exposed control mice.We analysed fertility parameters and global changes in the patterns of mice testis proteome by 2D-electrophoresis/mass spectrometry, along with bioinformatic analyses of dysregulated microRNAs, and their association with published data in human infertile patients.We detected a decrease in the potential fertility of exposed mice associated with changes in the expression of 18 proteins (10 up-regulated, 8 down-regulated). Functional analysis showed that 89% were involved in cell death. Furthermore, we found a group of 23 microRNAs/isomiRs (down-regulated) correlated with six of the up-regulated target proteins (DIABLO, PGAM1, RTRAF, EIF4E, IVD and CNDP2). Regarding this, PGAM1 up-regulation was validated by Western blot and mainly detected in Sertoli cells. Some of these microRNA/protein dysregulations were reported in human testis with spermatogenic failure.Overall, a chronic exposure to EDCs mixture in human males could potentially lead to spermatogenic failure through changes in microRNA expression, which could post-transcriptionally dysregulate mRNA targets that encode proteins participating in cell death in testicular cells. Finally, these microRNA/protein dysregulations need to be validated with other EDCs mixtures and concentrations.
This work was supported by grants from FONDECYT 1150352 to R.D.M., FONDECYT 3160273 to P.U-M and CONICYT 21120505 to J.B., Chile, and MINECO BFU2013-42164-R and BFU2017-87095-R to J. d. M., Spain