Prenatal exposure to endocrine disruptors induces trans-generational deregulation of microRNAs involved in the LIN28-LET-7-BLIMP1 pathway in male primordial germ cells

0428098 - BTÚ 2015 CN eng A - Abstract
Brieño-Enríquez, M.A. - López, J.G. - Cárdenas, D.B. - Guibert, S. - Děd, Lukáš - Cleroux, E. - Hourcade, J.D. - Pěknicová, Jana - Weber, M. - del Mazo, J.
Prenatal exposure to endocrine disruptors induces trans-generational deregulation of microRNAs involved in the LIN28-LET-7-BLIMP1 pathway in male primordial germ cells.
Abstracts of papers presented at the 2014 Cold Spring Harbor Asia Conference. Suzhou: Cold Spring Harbor Laboratory, 2014. s. 150-150.
[Epigenetics, chromatin and transcription. 05.05.2014-09.05.2014, Suzhou]
R&D Projects: GA ČR(CZ) GAP503/12/1834; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036
Keywords : primordial germ cells * microRNA * endocrine disruptor * methylation
Subject RIV: EB - Genetics ; Molecular Biology

Primordial germ cells (PGC) are the embryonic precursors of the germ cell linage, which are restricted to form only sperm and oocytes following their specification from pluripotent cells. PGC precursors are specified in the epiblast around 6.25 days post coitum (dpc), and around 7.25 dpc become identifiable in a 40 cell-cluster. Thereafter, PGC migrates through hindgut endoderm and colonize the genital ridges at day 10.5. PGC specification depends on interactions among various molecular factors including different microRNA and microRNA-regulated molecules. In the present study, we used a mouse model to evaluate the trans-generational (F1-F3) effects of endocrine disruptor with anti-androgenic effects vinclozolin (VCZ) administrated in two doses. We observed decreased fertility rate, higher apoptotic rate and histopathologic alterations in adult testis, PGC number reduction, increments of PGC apoptosis and changes in PGC gene expression. In the attempt to clarify the trans-generational transmition of the altered phenotypes, we performed the microRNA expression and DNA methylation analysis. We observed the significant alteration in the expression of multiple microRNA and microRNA-regulated genes which are important for PGCs specification, including LIN28, let-7 and BLIMP1. In the absence of microRNA-binding protein LIN28, microRNA let-7 binds to the 3´UTR of the Blimp1 mRNA to block its translation and prevent PGCs from developing. LIN28 binds to the let-7 family pri-miRNA loop to prevent processing of these precursor forms into the mature let-7 miRNA, allowing BLIMP1 translation, and permitting PGC specification. Therefore, trans-generational deregulation in the expression of factors involved in the Lin28-let-7-Blimp1 pathway can lead to specific VCZ-induced phenotype observed in our study. The possible mechanisms responsible for the trans-generational transmission of altered microRNA expression patterns can involve paramutations and/or altered DNA methylation.
Permanent Link: http://hdl.handle.net/11104/0236441