Nonsyndromic
cryptorchidism is a common multifactorial, condition with long-term risks of
subfertility and
testicular cancer. Revealing the causes of
cryptorchidism will likely improve prediction and prevention of adverse outcomes. Herein we provide our current perspective of
cryptorchidism complexity in a synthesis of cumulative clinical and translational data generated by ourselves and others. From our recent comparison of genome-wide association study (GWAS) data of
cryptorchidism with or without
testicular germ cell tumor, we identified RBFOX family genes as candidate susceptibility loci. Notably, RBFOX
proteins regulate production of
calcitonin gene-related peptide (CGRP), a sensory
neuropeptide linked to testicular descent in animal models. We also re-analyzed existing fetal testis transcriptome data from a rat model of inherited
cryptorchidism (the LE/orl strain) for enrichment of Leydig cell progenitor genes. The majority are coordinately downregulated, consistent with known reduced testicular
testosterone levels in the LE/orl fetus, and similarly suppressed in the gubernaculum. Using qRT-PCR, we found dysregulation of dorsal root ganglia (DRG) sensory transcripts ipsilateral to
undescended testes. These data suggest that LE/orl
cryptorchidism is associated with altered signaling in possibly related cell types in the testis and gubernaculum as well as DRG. Complementary rat and human studies thus lead us to propose a multi-level, integrated neuro-hormonal model of testicular descent. Variants in genes encoding RBFOX family
proteins and/or their transcriptional targets combined with environmental exposures may disrupt this complex pathway to enhance
cryptorchidism susceptibility. We believe that a systems approach is necessary to provide further insight into the causes and consequences of
cryptorchidism.