Seminar article
Environmental toxicology of testicular cancer

https://doi.org/10.1016/j.urolonc.2011.09.009Get rights and content

Abstract

Objective

Testicular cancer incidence appears to be increasing. In many regions, industrialization results in the production of potentially carcinogenic environmental toxins. We review the available data linking environmental toxins to testicular germ cell tumors (TGCT).

Methods

A PubMed review of the English literature was performed to identify studies evaluating the relationship between environmental toxins and TGCT.

Results

Many environmental toxins have been implicated in the development of TGCT, including organochlorines, polychlorinated biphenyls, polyvinyl chlorides, phthalates, marijuana, and tobacco. Variable levels of evidence exist and significant study design limitations preclude a definitive etiologic role for individual environmental toxins.

Conclusion

Environmental toxins may play an important but undetermined role in the development of TGCT. Further work is needed to evaluate specific toxins and TGCT carcinogenesis.

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.

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