The effects of chemotherapy with bleomycin, etoposide, and cis‐platinum on telomeres in rat male germ cells

Abstract

SUMMARYCo-administration of bleomycin, etoposide, and cis-platinum (BEP) has increased the 5-year survival rate of testis cancer patients to over 90%; however, this treatment induces chemotoxic effects on male germ cells. Treatment of male rats with BEP, using a similar schedule to that used in man, affects reproductive organ weights and sperm count, motility, and DNA integrity, as well as pup survival rates. Telomeres, specialized structures at the termini of chromosomes, play an important role in the maintenance of genetic stability. In previous studies, we demonstrated, using a spermatogonial cell line, that cis-platinum and bleomycin damage telomeres and that cis-platinum also inhibits telomerase activity. Our objective here was to test the hypothesis that in vivo exposure to the BEP regimen used to treat testis cancer targets telomeres in the male germ line. Adult male Brown Norway rats received chronic treatment with a BEP regimen. DNA double strand breaks were increased significantly in zygotene germ cells, as assessed by c-H2AX immunofluorescence. Interestingly, treatment with this BEP regimen increased c-H2AX foci in the telomere region of zygotene spermatocytes, but not in other germ cell types, such as pachytene cells, round spermatids, or elongating spermatids. Mean telomere lengths were reduced in zygotene, pachytene, round spermatid, elongating spermatid and cauda epididymal spermatozoa compared with the saline control group. Thus, telomere lengths did not recover during germ cell development. These studies demonstrate that BEP treatment is associated with an effect on telomeres.

Effect of Bleomycin, Etoposide, and Cisplatin Treatment on Spermatogonia Cell and Malondialdehyde Level in Male Rats

“…Exposure to BEP chemotherapy can cause sperm DNA damage, induce the breakdown of single and double strand DNA, reduce chromatin density, induce telomere shortening in the spermatogenesis stage, damage to seminiferous tubular structures and testicular organs, and cause change in hormone levels in the blood that occurs after 3 to 6 months of BEPchemotherapy. 10,11 This study shows similar results, where in the second cycle of BEP chemotherapy, severe abnormalities begin to appear. The content of germ cells in the tubules has decreased, accompanied by immature germ cells that enter the lumen (Figure 2 (P-2, P-3)).…”

“…9 Exposure to BEP chemotherapy can cause sperm DNA damage, induce the breakdown of single and double strand DNA, decrease chromatin density, induce telomere Effect of Bleomycin, Etoposide, and Cisplatin Treatment on Spermatogonia Cell and Malondialdehyde Level in Male Rats shortening in the spermatogenesis stage, damage to seminiferous tubular structures and testicular organs that occur after 3 to 6 months of administration chemotherapy BEP. 10,11 Prolonged chemotherapy can also stimulate the formation of expression of oxidative stress responses in the testes, the end result of which can induce damage from the germ cell pathway. 5 Until now it has not been known with certainty that damage has occurred to the testes due to the administration of BEP chemotherapy, so that intervention on patients undergoing chemotherapy cannot be known with certainty, so researchers want to examine the start of damage to the testes due to BEP chemotherapy.…”

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

“…Moreover, combining new agents with (cisplatin-based) chemotherapy may hypothetically be beneficial in terms of further enhancing sensitivity of GCTs towards cytotoxic treatment, which potentially may allow for reduced intensity treatment sparing patients from acute and long-term toxicity, which includes renal impairment, decreased immunity to infections, gastrointestinal disorders, and hearing loss (Dasari & Tchounwou, 2014), telomere damage in mature spermatozoa (Liu et al, 2015), and impaired reproductive function in young male adults (Maselli et al, 2012(Maselli et al, , 2013.…”

An Association Study between Longitudinal Changes of Leukocyte Telomere and the Risk of Azoospermia in a Population of Iranian Infertile Men

“…Currently, a survey has demonstrated that SLT is connected with the motility and vitality of sperm, as well as sperm DNA fragmentation [28] . Another investigation on adult male Brown Norway rats has indicated an association between chemotherapy treatment and the reduction of the telomere length in spermatocytes [29] . Another study has found that the exposure to anticancer drugs may have a function in male infertility through the induction of telomere dysfunction [30] .…”