Preventing/Reversing Adverse Effects of Endocrine Disruption on Mouse Testes by Normalizing Tissue Resident VSELs.

Abstract

Reproductive health of men is declining in today's world due to increased developmental exposure to endocrine-disrupting chemicals (EDCs). We earlier reported that neonatal exposure to endocrine disruption resulted in reduced numbers of seminiferous tubules in Stage VIII, decreased sperm count, and infertility along with testicular tumors in 65% of diethylstilbestrol (DES) treated mice. Epigenetic changes due to EDCs, pushed the VSELs out of a quiescent state to enter cell cycle and undergo excessive self-renewal while transition of c-KIT- stem cells into c-KIT + germ cells was blocked due to altered MMR axis (Np95, Pcna, Dnmts), global hypomethylation (reduced expression of 5-methylcytosine) and loss of imprinting at Igf2-H19 and Dlk1-Meg3 loci. The present study was undertaken to firstly show similar defects in FACS sorted VSELs from DES treated testis and to further explore the reversal of these testicular pathologies by (i) oral administration of XAR (a nano-formulation of resveratrol) or (ii) inter-tubular transplantation of mesenchymal stromal cells (MSCs). Similar defects as reported earlier in the testes were evident, based on RNAseq data, on FACS sorted VSELs from DES treated mice. Both strategies were found effective, improved spermatogenesis, increased number of tubules in Stage VIII, normalized numbers of VSELs and c-KIT + cells, improved epigenetic status of VSELs to restore quiescent state, and reduced cancer incidence from 65% after DES to 13.33% and 20% after XAR treatment or MSCs transplantation respectively. Results provide a basis for initiating clinical studies and the study falls under the umbrella of United Nations Sustainable Development Goal 3 to ensure healthy lives and well-being for all of all ages.