Cryptorchidism, characterized by the presence of one (unilateral) or both (bilateral) undescended testes, is a common male urogenital defect. Cryptorchidism can lead to male infertility, testicular cancer being the most extreme clinical symptom, as well as psychological issues of the inflicted individual. Despite this, both knowledge about the aetiology of cryptorchidism and the mechanism for cryptorchidism-induced male infertility remain limited. In this present study, by using an artificial cryptorchid mouse model, we investigated the effects of surgery-induced cryptorchidism on spermatogenic cells and seminiferous epithelial cycles. We found that surgery-induced cryptorchidism led to a reduced testicular weight, aberrant seminiferous epithelial cycles and impaired spermatogenesis characterized by degenerating spermatogenic cells. We also observed multinucleated giant cells after surgery-induced cryptorchidism. Transmission electron microscopy, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and western blot assays demonstrated cryptorchidism-induced apoptosis of spermatogenic cells. Moreover, we identified the occurrence of autophagy in germ cells after surgery-induced cryptorchidism. Interestingly, apoptosis and autophagy were synchronous, suggestive of their synergetic roles in promoting germ cell death. Our results provide novel insights into the cryptorchidism-induced male infertility, thereby contributing to the development of male contraceptive strategies as well as treatment options for male infertility caused by cryptorchidism.

Cryptorchidism represents one of the most common human congenital anomalies. In most cases, its etiology remains unclear and seems to be multifactorial. In the present study, a pair of monozygotic twins discordant for cryptorchidism was identified. Twin zygosity was confirmed by microsatellite genotyping. Whole exome sequencing and methylated DNA immunoprecipitation sequencing (MeDIP-Seq) of DNA extract from leucocytes were performed to, respectively, evaluate their exomes and epigenomes. No differences in exome sequencing data were found between the twins after validation. MeDIP-Seq analysis detected 5,410 differentially hypermethylated genes and 2,383 differentially hypomethylated genes. Bioinformatic analysis showed that these genes belonged to several biological processes and signaling pathways, including regulation of actin cytoskeleton, which has been previously implicated in the etiology of cryptorchidism. The findings of the present study suggest that non-genetic factors might contribute to the pathogenesis of cryptorchidism.

Exposure of male Albino Swiss rats to the nonsteroidal antiandrogen flutamide during the period from gestational day (d) 10 to birth resulted in feminisation of the external genitalia and the suppression of growth of the male reproductive tract. In adulthood, testes were found to be located in diverse positions. True cryptorchidism occurred in 10% of cases, whereas 50% of testes descended to the scrotum and 40% were located in a suprainguinal ectopic region. Varying degrees of tubule abnormality were seen in the testes of flutamide-treated animals, ranging from completely normal tubules with full spermatogenesis (and the expected frequency of the stages of spermatogenesis) to severely abnormal tubules lined with Sertoli cells only. For each individual testis, the overall severity of tubule damage was strongly correlated with its adult location, with intra-abdominal testes worst affected and scrotally-located testes least; only the latter contained normal tubules. Similarly, intra-abdominal testes were the smallest in weight and contained the least testosterone. By contrast, postnatal treatment of male rats with flutamide from birth to postnatal d 14 did not impair development of the external genitalia, the process of testicular descent or adult spermatogenesis. These findings confirm that androgen blockade during embryonic development interferes with testicular descent but also demonstrate that (1) prenatal flutamide treatment per se has a detrimental effect on adult testis morphology but (2) the degree of abnormality of the testes is strongly influenced by location.

Prior studies have suggested that the risk of testicular cancer among dizygotic twins may exceed that among monozygotic twins or the general population. Cryptorchidism is associated with testicular cancer and twinship, and therefore might potentially explain the findings of the prior studies. In 1993-1994, when they were 66 to 77 years of age, 14,326 twin individuals in the National Academy of Sciencies-National Research Council Twin Registry were interviewed by telephone. A history of testicular cancer was reported by 5 (0.08%) of 5951 monozygotic twins and 11 (0.16%) of 6992 dizygotic twins. Follow-up interviews concerning testicular cancer risk factors and treatment were able to be administered to 4 of the monozygotic and 9 of the dizygotic twins reporting testicular cancer. A history of cryptorchidism was reported in the follow-up interview by only one dizygotic twin. Our data agree with the results of prior studies reporting a more frequent occurrence of testicular cancer among dizygotic than monozygotic twins. Although somewhat limited by small numbers, our study also suggests that the findings of increased testicular cancer in dizygotic twins are not explained simply by increased occurrence of cryptorchidism in twins.