Perspective: A Neuro-Hormonal Systems Approach to Understanding the Complexity of Cryptorchidism Susceptibility

Abstract

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.

Endocrine Disrupting Chemicals Interfere With Leydig Cell Hormone Pathways During Testicular Descent in Idiopathic Cryptorchidism

“…To conclude, experimental and epidemiological studies support the hypothesis of a deleterious role for fetal exposure to a cocktail of endocrine disruptors during the testicular descent; those compounds, acting as xenoestrogens and/or antiandrogens, may disrupt the secretion and/or action of INSL3 and testosterone, the two Leydig cell hormones, regulating testis descent, and lead to cryprorchidism in case of a genetic susceptibility context as recently suggested by Barthold and Ivell (71). However, direct evidence to support such a pathophysiological link explaining idiopathic UDT, remain scares.…”

New Insights into the Role of INSL-3 in the Development of Cryptorchidism

“…In the human fetus, the synthesis of INSL3 begins early on, following gonadal sex differentiation, at 7 weeks of gestation. INSL3 also acts in the manner of a significant biomarker of the Leydig cell differentiations in the male fetus [ 6 , 10 ].…”

“…The main factors involved in the testicular descent are hormones (androgens), the genitofemoral nerve, and the most quoted insulin-like hormone 3 (INSL3). INSL3 controls the transabdominal part of testicular descent, playing a role in the gubernacular swelling reaction [ 5 , 6 , 7 ]. This literature review aims to discuss and analyze the importance of INSL3 and its mutation into cryptorchidism in both human and animal models.…”

To RNA‐binding and beyond: Emerging facets of the role of Rbfox proteins in development and disease

“…Interestingly, meta-analysis of genome-wide association studies (GWAS) from subjects with testicular germ cell tumor has correlated suggestive intragenic single nucleotide polymorphisms (SNPs) in genes encoding Rbfox proteins with cryptorchidism susceptibility (Wang et al, 2018) (Box 1). Thus, Barthold and Ivell (2018) have proposed that a neuro-hormonal signaling network regulates testicular descent via crosstalk between neuronal and reproductive tissues: on the one hand, Rbfox is expressed through autoregulation and regulation by androgens, while on the other, Rbfox proteins regulate the alternative splicing of Calca, as mentioned previously, in the dorsal root ganglia to generate calcitonin gene-related peptide (CGRP), which is released by sensory nerves innervating the gubernacular ligament, which connects the testis to the body wall in the inguinal region, and is indispensable for testicular descent.…”