Abstract
Humans are environmentally exposed not only to single endocrine-disrupting chemicals (EDCs) but to mixtures that affect their reproductive health. In reproductive tissues, microRNAs (miRNAs) are emerging as key targets of EDCs. Here, we analysed changes in the testis “miRNome” (and their biogenesis mechanism) in chronically exposed adult mice to a cocktail of five EDCs containing 0.3 mg/kg-body weight (BW)/day of each phthalate (DEHP, DBP, BBP) and 0.05 mg/kg-BW/day of each alkylphenol (NP, OP), from conception to adulthood. The testis “miRNome” was characterised using next-generation sequencing (NGS). Expression levels of genes involved in miRNA biogenesis were measured by RT-qPCR, as well as several physiological and cytological parameters. We found two up-regulated, and eight down-regulated miRNAs and thirty-six differentially expressed isomiRs along with an over-expression of Drosha, Adar and Zcchc11. A significant decrease of intratesticular estradiol but not testosterone was detected. Functional analysis showed altered spermatogenesis, germ cell apoptosis and negative correlation of miR-18a-5p with Nr1h2 involved in the deregulation of the steroidogenesis pathway. Here, we present the first association between miRNA/isomiRs deregulation, their mechanisms of biogenesis and histopathological and hormonal alterations in testes of adult mice exposed to a mixture of low-dose EDCs, which can play a role in male infertility.
Highlights
Endocrine-disrupting chemicals (EDCs) have been described as “an exogenous substance or mixture that alters function(s) of the endocrine system and causes adverse health effects in an intact organism, or its progeny, or populations”[1, 2]
Since we found out that some genes that encode proteins involved in the biogenesis and processing of miRNAs were deregulated in the testes of mice exposed to the endocrine-disrupting chemicals (EDCs) mixture, we decided to perform next-generation sequencing (NGS) of sncRNA to analyse the miRNome in both exposed and control mice
By RT-qPCR, we found that Nr1h2 levels were two-fold higher in testes of mice exposed to EDCs mixture, which were negatively correlated with miR-18a-5p (Fig. 7A,B), suggesting a mechanism of estradiol downturn by various pathways and associated with loss of miR-18a-5p induced by the exposure to the EDCs mixture (Fig. 7C)
Summary
Endocrine-disrupting chemicals (EDCs) have been described as “an exogenous substance or mixture that alters function(s) of the endocrine system and causes adverse health effects in an intact organism, or its progeny, or (sub) populations”[1, 2]. Humans are chronically exposed to low-doses of combinations of alkylphenols and phthalates throughout their lives To support this statement, there are data showing that these chemicals are present in human samples such as blood, breast milk, urine, amniotic fluid, and semen[10], and even in complex developmental organs such as the placenta[11]. MicroRNAs (miRNAs) are small, endogenous non-coding RNAs (ncRNAs), usually 20–25 nucleotides long and evolutionarily well-conserved across metazoans[12] They comprise a mechanism of negative regulation of gene expression in a sequence-specific manner that is present in all cells and developmental processes and could play a part in diverse pathologies. Some aspects of their processing are still poorly understood, most of their basic biogenesis including the canonical and functional variants (isomiRs), is well established[13, 14]
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