Genetic and Environmental Determinants of Cryptorchidism and Testicular Cancer in Dogs

Cryptorchidism and testicular cancer in dogs are increasingly recognized as multifactorial conditions influenced by a combination of genetic, environmental, and epigenetic factors. While clinical associations between these disorders are well established, their underlying causes remain incompletely defined. Advances in molecular biology and comparative research have provided valuable insights, although significant gaps in knowledge persist. 

Genetic Basis of Cryptorchidism in Dogs 

Cryptorchidism exhibits a strong genetic component in both humans and dogs. Several genes involved in testicular descent have been identified, with insulin-like hormone 3 (INSL3) and its receptor RXFP2 playing central roles. INSL3 is responsible for the transabdominal phase of testicular descent by promoting gubernacular development, while RXFP2 mediates its biological effects^1,2. 

In dogs, genome-wide association studies have identified variants in RXFP2 and other candidate genes associated with cryptorchidism [148–150]. Interestingly, some studies have reported that the expression of RXFP2 is significantly reduced or absent in cryptorchid testes, suggesting that loss-of-function mutations in this receptor may be a key mechanism underlying the condition^1,3. 

Additional genes, including HMGA2, MMP9, ADAMTS20, and MID1IP1, have also been implicated in canine cryptorchidism, particularly in relation to extracellular matrix remodeling and gubernacular development ^1,3. However, the genetic architecture of the condition is complex, and no single mutation fully explains its occurrence. 

Genetic Factors in Testicular Cancer 

In contrast to cryptorchidism, the genetic basis of testicular cancer in dogs is less well defined. While certain breeds show a higher prevalence of testicular tumors, specific gene mutations have not been conclusively identified. This suggests a polygenic mode of inheritance, similar to that observed in human testicular germ cell tumors⁴. 

In humans, multiple susceptibility loci have been identified through genome-wide association studies, with genes such as KITLG, DMRT1, and TERT playing important roles in germ cell development and tumorigenesis⁴. Although these findings cannot be directly extrapolated to dogs, they provide a useful framework for future research. 

Environmental Influences and Chemical Exposure 

Environmental factors are increasingly recognized as important contributors to both cryptorchidism and testicular cancer. In humans, exposure to endocrine-disrupting chemicals, pesticides, and industrial pollutants has been associated with an increased risk of testicular abnormalities⁵. Similar associations have been proposed in dogs, although direct evidence remains limited. 

One study reported higher concentrations of diethylhexyl phthalate (DEHP) and polychlorinated biphenyls in canine testes, which were correlated with histopathological alterations⁶. These findings suggest that environmental contaminants may interfere with normal testicular development and function, potentially contributing to both cryptorchidism and tumor formation. 

Role of Epigenetic Mechanisms 

Epigenetic modifications, including DNA methylation, histone modifications, and microRNA expression, represent a potential link between genetic predisposition and environmental exposure. In human testicular tumors, seminomas are characterized by a globally unmethylated DNA pattern, while non-seminomas exhibit more complex methylation profiles⁷. 

In dogs, recent studies have identified alterations in histone acetylation associated with cryptorchidism. A single nucleotide polymorphism in the KAT6A gene was found to reduce global H3K9 acetylation, leading to widespread changes in gene expression, including genes involved in testicular descent such as INSL3 and RXFP2⁸. These findings highlight the importance of epigenetic regulation in the pathogenesis of cryptorchidism. 

Developmental Timing and Susceptibility 

One important distinction between dogs and humans is the timing of germ cell development. In dogs, the differentiation of gonocytes into spermatogonia continues for several weeks after birth, extending up to 16 weeks postnatally¹. This prolonged developmental window may increase susceptibility to environmental and hormonal disruptions during early life. 

In contrast, in humans, much of this differentiation occurs prenatally, limiting the window of vulnerability¹. This difference may partly explain the higher prevalence of certain tumor types, such as Sertoli cell tumors, in dogs compared to humans. 

Lack of a Unified Genetic Model 

Despite extensive research, there is currently no clear evidence of a shared genetic basis linking cryptorchidism and testicular cancer. Studies in humans have shown that major susceptibility loci for testicular cancer do not significantly differ in individuals with or without cryptorchidism. Similarly, family history of cryptorchidism does not appear to increase the risk of testicular cancer, suggesting that these conditions may arise from distinct, albeit overlapping, pathways¹. 

Clinical and Breeding Implications 

From a veterinary perspective, the multifactorial nature of cryptorchidism and testicular cancer has important implications for breeding and clinical management. Dogs with cryptorchidism should not be used for breeding due to the hereditary nature of the condition. Additionally, awareness of environmental risk factors may help reduce exposure to potential endocrine disruptors. 

Conclusion 

Cryptorchidism and testicular cancer in dogs are complex conditions influenced by an interplay of genetic, environmental, and epigenetic factors. While significant progress has been made in understanding their pathogenesis, many questions remain unanswered. Continued research is essential to identify definitive mechanisms and improve preventive and therapeutic strategies in veterinary practice. 

Reference 

1. Soto-Heras S, Reinacher L, Wang B, Oh JE, Bunnell M, Park CJ, Hess RA, Ko CJ. Cryptorchidism and testicular cancer in the dog: unresolved questions and challenges in translating insights from human studies. Biology of reproduction. 2024 Aug;111(2):269-91. https://academic.oup.com/biolreprod/article-pdf/111/2/269/58824383/ioae075.pdf 

2. Dicke AK, Albrethsen J, Hoare BL, Wyrwoll MJ, Busch AS, Fietz D, Pilatz A, Bühlmann C, Juul A, Kliesch S, Gromoll J, Bathgate RAD, et al. Bi-allelic variants in INSL3 and RXFP2 cause bilateral cryptorchidism and male infertility. Hum Reprod 2023; 38:1412–1423. https://research.regionh.dk/en/publications/bi-allelic-variants-in-insl3-and-rxfp2-cause-bilateral-cryptorchi/ 

3. Blades M, Freyer J, Donner J, Foran RC, Forman OP. Large scale across-breed genome-wide association study reveals a variant in HMGA2 associated with inguinal cryptorchidism risk in dogs. PloS One 2022; 17:e0267604. https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0267604&type=printable 

4. Pluta J, Pyle LC, Nead KT, Wilf R, Li M, Mitra N, Weathers B, D’Andrea K, Almstrup K, Anson-Cartwright L, Benitez J, Brown CD, et al. Identification of 22 susceptibility loci associated with testicular germ cell tumors. Nat Commun 2021; 12:4487. https://www.nature.com/articles/s41467-021-24334-y.pdf 

5. Yazici S, Del Biondo D, Napodano G, Grillo M, Calace FP, Prezioso D, Crocetto F, Barone B. Risk factors for testicular cancer: environment, genes and infections—is it all?. Medicina. 2023 Apr 7;59(4):724. https://www.mdpi.com/1648-9144/59/4/724 

6. Sumner RN, Byers A, Zhang Z, Agerholm JS, Lindh L, England GCW, Lea RG. Environmental chemicals in dog testes reflect their geographical source and may be associated with altered pathology. Sci Rep 2021; 11:7361. https://www.nature.com/articles/s41598-021-86805-y.pdf 

7. Shen H, Shih J, Hollern DP, Wang L, Bowlby R, Tickoo SK, Thorsson V, Mungall AJ, Newton Y, Hegde AM, Armenia J, Sanchez-Vega F, et al. Integrated molecular characterization of testicular germ cell tumors. Cell Rep 2018; 23:3392–3406. https://www.cell.com/cell-reports/pdfExtended/S2211-1247(18)30785-X 
8. Stachowiak M, Nowacka-Woszuk J, Szabelska-Beresewicz A, Zyprych-Walczak J, Krzeminska P, Sosinski O, Nowak T, Switonski M. A massive alteration of gene expression in undescended testicles of dogs and the association of KAT6A variants with cryptorchidism. Proc Natl Acad Sci U S A 2024; 121:e2312724121. https://www.pnas.org/doi/pdf/10.1073/pnas.2312724121