US EPA

3860092 

Journal Article 

Chronic low-dose exposure to a mixture of environmental endocrine disruptors induces microRNAs/isomiRs deregulation in mouse concomitant with intratesticular estradiol reduction 

Buñay, J; Larriba, E; Moreno, RD; Del Mazo, J 

2017 

1 

Scientific Reports
EISSN: 2045-2322 

Nature Publishing Group 

LONDON 

7 

1 

3373 

English 

28611354 

10.1038/s41598-017-02752-7 

WOS:000403140000044 

http://www.nature.com/articles/s41598-017-02752-7
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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. 

biological marker; endocrine disruptor; estradiol; microRNA; RNA isoform; animal; apoptosis; C57BL mouse; dose response; drug effect; female; gene expression regulation; genetics; germ cell; male; male infertility; metabolism; mouse; pathology; reproduction; spermatogenesis; testis; Animals; Apoptosis; Biomarkers; Dose-Response Relationship, Drug; Endocrine Disruptors; Estradiol; Female; Gene Expression Regulation; Germ Cells; Infertility, Male; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Reproduction; RNA Isoforms; Spermatogenesis; Testis