Type 1 diabetes upregulates metastasis-associated protein 1- phosphorylated histone 2AX signaling in the testis.

Under the sustained hyperglycemic state, oxidative stress induces irreparable DNA double-strand breaks resulting in germ cell death and testicular atrophy. Although molecular mechanisms underlying DNA damage repair in testicular cells are gradually getting unraveled, the effects on DNA double-strand breaks sensing are not precisely known. In this study, using streptozotocin-induced type 1 diabetic rats, we report that hyperglycemic state for one month or three months does not increase the levels of ataxia telangiectasia mutated (ATM) protein- an upstream kinase responsible for the phosphorylation of histone 2AX (Ɣ-H2AX)- after the formation of DNA double-strand breaks. The ATM expression is seminiferous epithelial stage-dependent in spermatogonia and primary spermatocytes, and the pattern of stage-dependent expression varies in diabetic rats, especially after three-month-long diabetes. However, the levels of metastasis-associated protein-1 (MTA1), an essential protein for ATM function, increase although not in a time-dependent manner. The amount of DNA double-strand breaks increases in a time- and stage-dependent manner as indicated by increased Ɣ-H2AX levels, especially in spermatogonia and primary spermatocytes, and in late spermatids in some tubular stages. Although ATM levels do not increase in diabetic rats, protein is expressed more or less in same testicular cells in which Ɣ-H2AX is expressed indicating that ATM might play a vital role in the phosphorylation of the histone. We conclude that diabetes upregulates MTA1-Ɣ-H2AX signaling in diabetic rat testis as a response to time-dependent increases in DNA double-strand breaks.