Urologic Oncology: Seminars and Original Investigations
Seminar articleEnvironmental toxicology of testicular cancer
Introduction
In nearly all developed countries, testicular germ cell tumors (TGCT) are the most common solid organ neoplasm of men age 20–39 years [1]. Globally, the highest incidence rates occur in Western and Northern Europe, followed by Australia and Northern America, with the lowest rates in Eastern Asia and Africa [2]. Inexplicably, the incidence of testicular cancer in the United States has increased by 44% from 1973 to 1998 [3]. Similar trends have been observed in Europe, Canada, South America, Israel, and Australia with plateauing or decreasing rates in East Asia [4]. Baseline elevated risk of developing TGCT may be secondary to ethnic susceptibility, congenital factors, or an increased exposure to environmental toxins through industrialization. Increasing incidence rates are likely due to changes in environmental exposure [5].
The etiology of TGCT remains an intense area of investigation. As a sight of pluripotent stem cells in the male, initiation of testis cancer may be secondary to aberrant cellular development during stem cell renewal or maturation [6]. The most consistently identified factor associated with testis cancer is cryptorchidism, which increases a man's risk of TGCT development by nearly 5-fold (RR 4.8) [7], [8]. Other risk factors have been identified, such as subfertility (RR 1.68 [9]), although the data is not as robust. Additionally, men with a previous TGCT have an estimated 12-fold relative risk of developing a tumor in the contralateral testicle [10]. Although men with a first degree relative (brother or father) have a 4- to 10-fold increased risk of developing testis cancer [11], only 1% of all TGCT are suspected to have a hereditary etiology [12] and it is difficult to separate genetics from a common environmental exposure or lifestyle factor. Thus, the contribution of environmental exposures to the development of testis cancer remains an important and underappreciated area of research.
The testis may be susceptible to environmental toxins from external and internal routes. The anatomical location of the testis in the scrotum may play an important role in carcinogenesis, as the testes are largely unprotected from external toxins such as extreme heat exposure, γ-radiation and electromagnetic fields [13]. For environmental toxins to reach the testicular germ cells, they must pass through the blood–testis barrier that resides between cords of the seminiferous tubules. The blood–testis barrier has been incompletely studied but there does not appear to be a specific molecular size that is restricted from passing through the barrier as diffusion is more related to lipid solubility [14]. The first cell population encountered when crossing from the blood into the testis is the androgenic Leydig cells. These cells may be particularly sensitive to estrogen-like compounds, potentially contributing to development of testicular neoplasms due to hormonal stimulation from environmental endocrine disruptors [15].
Section snippets
Agents that may cause testis cancer
An agent may increase the risk of developing TGCT by several mechanisms (Table 1). First, direct damage to DNA may lead to germ cell mutations, which subsequently results in testicular cancer (genotoxic). We are not aware of any testis-specific genotoxic agents that have been described. Second, the environmental agent may affect the hormonal activity of the testis and alter normal cellular development (endocrine disruptors). A particularly susceptible time period for testicular germ cells is
Organochlorines and polychlorinated biphenyls
The best studied environmental carcinogens are the organochlorine pesticides, specifically p,p'-DDE (a derivative of DDT) and octachloro-4,7-methanohydroindane (referred to as chlordane). The agent p,p'-DDE is a potent androgen receptor antagonist, which was commonly used as a pesticide until it was banned in the 1970s–1980s [17]. In a large study of Finnish men, exposure to insecticides was associated with an increased risk of seminoma [18]. In a small case-control study of Norwegian men (49
Temperature
As the testes are outside of the body, they may be more vulnerable to environmental temperatures. Occupational exposure to extreme conditions (>80°F or <60°F) has been demonstrated to significantly increase the risk of TGCT [39]. Yet, a case-control study of 323 men with TGCT did not demonstrate a higher rate of hot tub, sauna, or tight-fitting underwear use [40].
Biology of carcinogen metabolism
TGCTs are not uniformly distributed among races and ethnicities [1]. While the genetic causes that contribute to the racial asymmetry of testis cancer are unknown, one possibility may involve the expression and activity of carcinogen metabolizing genes. An example is cytochrome P4501A2 (CYP1A2). Low CYP1A2 activity conferred increased risk to TGCT formation (OR 2.2, 95% CI 1.23–3.62) in 184 men with TGCT compared with 194 controls [41]. The association of low CYP1A2 activity was seen with NSGCT
Limitations and future directions
There is a large gap in our knowledge of environmental toxicology and carcinogenesis. The majority of reports are historic epidemiologic case-control studies based on environmental exposure through occupations. Common design flaws include small cohorts, not controlling for other risk factors (e.g., cryptorchidism), and lack of plasma levels of the suspected carcinogen.
Further, for many suggested toxins a quantifiable assay is not available. The role of host genetics and pharmacogenomics are
Conclusion
The incidence of testis cancer is increasing and is associated with global industrialization. Few agents have been directly associated with an increased risk of developing testis cancer. Future epidemiologic, toxicologic, and mechanistic studies are needed to identify and quantify the risk of developing TGCT due to specific environmental toxins.
References (42)
- et al.
Global trends in testicular cancer incidence and mortality
Eur Urol
(2011) - et al.
Occurrence of testis tumor in undescended testes
J Urol
(1959) - et al.
Changes in PCB serum concentrations among capacitor manufacturing workers
Environ Res
(1992) - et al.
Testicular cancer and occupational exposures with a focus on xenoestrogens in polyvinyl chloride plastics
Chemosphere
(2000) - et al.
Marijuana extracts possess the effects like the endocrine disrupting chemicals
Toxicology
(2005) - et al.
Effects of cannabinoids on prolactin and gonadotrophin secretion: Involvement of changes in hypothalamic gamma-aminobutyric acid (GABA) inputs
Biochem Pharmacol
(1998) - et al.
Maternal smoking during pregnancy and testicular cancer in the sons: A nested case-control study and a meta-analysis
Eur J Cancer
(2009) SEER Cancer Statistics Review, 1975–2008National Cancer Institute; 2011; based on November 2010 SEER data submission, posted to the SEER web site, 1
- et al.
Trends in the incidence of testicular germ cell tumors in the United States
Cancer
(2003) - et al.
International trends in the incidence of testicular cancer, 1973–2002
Cancer Epidemiol Biomarkers Prev
(2010)
Incidence of testicular cancer in the United States: Has the epidemic begun to abate?
Am J Epidemiol
Testicular germ cell tumours: Predisposition genes and the male germ cell niche
Nat Rev Cancer
Clinical epidemiology of testicular germ cell tumors
World J Urol
The association risk of male subfertility and testicular cancer: A systematic review
PLoS One
Risk of contralateral testicular cancer: A population-based study of 29,515 U.S. men
J Natl Cancer Inst
Familial risk in testicular cancer as a clue to a heritable and environmental etiology
Br J Cancer
Familial testicular germ cell tumors in adults: 2010 Summary of genetic risk factors and clinical phenotype
Endocr Relat Cancer
Testicular cancer and electromagnetic fields (EMF) in the workplace: Results of a population-based case-control study in Germany
Cancer Causes Control
The functional significance of the blood–testis barrier
J Andrology
Environmental estrogens: Roles in male reproductive tract problems and in breast cancer
Rev Environ Health
Genetic polymorphism and toxicology—with emphasis on cytochrome p450
Toxicol Sci
Cited by (16)
Serum polychlorinated biphenyl (PCB) levels and risk of testicular germ cell tumors: A population-based case-control study in Connecticut and Massachusetts
2021, Environmental PollutionCitation Excerpt :The results, however, have been inconsistent (Biggs et al., 2008; Cohn et al., 2010; Hardell et al., 2003; Kelce et al., 1995; Longnecker et al., 1997). Studies have shown that PCBs could affect the differentiation of normal germ cells by obstructing post-transcriptional regulation or cause epigenetic changes due to their hormonal activities and/or enzyme inducibility (Abelsohn et al., 2002; Bouskine et al., 2008; Dorssers et al., 2019; Jensen et al., 1995; Jorgensen et al., 2015; Meeks et al., 2012; Youngson and Whitelaw 2008), which could produce potential harmful effects on the human reproduction system. Some have suggested that risk of TGCT may vary by specific type of PCB congeners (Hardell et al., 2006; McGlynn et al., 2009; Paoli et al., 2015; Purdue et al., 2009).
Epidemiology and Diagnosis of Testis Cancer
2015, Urologic Clinics of North AmericaCitation Excerpt :There is a growing body of evidence implicating toxic exposures and an increased risk of testicular cancer. The main substances with a potential association with testicular cancer include organochlorines, polychlorinated biphenyls, polyvinyl chlorides, phthalates, marijuana, and tobacco.13,14 Prenatal estrogen exposure has been implicated as a risk factor as well, but remains controversial.15,16
Epigenetic dimension of oxygen radical injury in spermatogonial epithelial cells
2015, Reproductive ToxicologyCitation Excerpt :However, the presence of specialized anti-oxidant machinery within the cells helps them to survive and grow unaffected in these complex conditions. In-spite of this exclusive protective mechanism accumulation of free radicals beyond a metabolic threshold interrupts the genome regulatory cascade of these frequently dividing cells [32]. Apart from exogenous pro-oxidant stress, epigenetic modifications under hypoxic conditions may also significantly disturb the pool of developing male germ cells [33].
Changes in epidemiologic features of testicular germ cell cancer: Age at diagnosis and relative frequency of seminoma are constantly and significantly increasing
2014, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :A number of environmental toxins, including organochlorines, polychlorinated biphenyls, polyvinyl chlorides, phthalates, diethylstilbestrol, and also viruses, have been postulated to interfere with the pathogenesis of GCT. However, a definitive etiologic role for these toxins has not been documented yet [25], and so the histologic subtype shift as reported herein can hardly be attributed to the influence of these agents. There is still an incomplete knowledge about the differential morphogenesis of seminoma and nonseminomas.
Trends in age and histology of testicular cancer from 1980-2019: A single-center study
2020, Tohoku Journal of Experimental MedicineDisease characteristics and treatment outcome of testicular germ cell tumors treated with platinum-based regimens
2018, Journal of the College of Physicians and Surgeons Pakistan