The environment and male reproductive system: the potential role and underlying mechanisms of cadmium in testis cancer

Abstract

Cadmium is a known human carcinogen, and has been shown to profoundly affect male reproductive function, at multiple levels, by exerting both endocrine and non-endocrine actions. Nevertheless, the potential role of cadmium in the etiology of testis cancer has been scantly investigated in humans, and, currently, available epidemiological observational studies are insufficient to draw definitive conclusions in this regard. On the contrary, experimental studies in laboratory animals demonstrated that cadmium is a strong inducer of testis tumors, mostly represented by benign Leydig cell adenoma; moreover, malignant transformation was also reported in few animals, following cadmium treatment. Early experimental studies in animals proposed an endocrine-dependent mechanism of cadmium-induced testis tumorigenesis; however, more recent findings from cell-free assays, in vitro studies, and short-term in vivo studies, highlighted that cadmium might also contribute to testis tumor development by early occurring endocrine-independent mechanisms, which include aberrant gene expression within the testis, and genotoxic effects, and take place well before the timing of testis tumorigenesis. These endocrine-independent mechanisms, however, have not been directly investigated on testis tumor samples retrieved from affected, cadmium-treated animals so far. The present review focuses on the relationship between cadmium exposure and testis cancer, by reporting the few epidemiological observational human studies available, and by providing animal-based experimental evidences of cadmium implication in the pathogenesis and progression of testis tumor. Moreover, the relevance of experimental animal studies to human cadmium exposure and the translational potential of experimental findings will be extensively discussed, by critically addressing strengths and weaknesses of available data.

Keywords:

• Environment
• cadmium
• testis cancer
• genetic instability
• endocrine

Acknowledgments

The authors sincerely thank the Editor and anonymous independent reviewer selected by the Editor, for critically reviewing the manuscript and for the valuable comments received, which provided significant scientific contribution to improve the quality of the article.

Authors’ contributions

CdA conceived and developed the manuscript in all its aspects, performed the literature search, wrote the manuscript, and conceived and prepared tables and figures. GG substantially contributed to the writing and revision of the section on in vivo studies in animals. DM, FG and NV substantially contributed to the writing and revision of the section on epidemiological studies in humans. MP contributed to the preparation of tables and figures. MN contributed to a throughout literature search for updates. RSA, CS and CP contributed to manuscript drafting and helped to revise the final version. AC critically reviewed and revised the manuscript. RP is the principal investigator, helped conceive and supervised the manuscript drafting, and critically reviewed and revised it for important intellectual content. All authors read and approved the final manuscript.

Declaration of interest

Authors take full accountability for the writing and content of this academic publication and acknowledge that this review article was not prepared at any request and views and opinions expressed in the article are those of the contributing authors. The author’s affiliation is as shown on the Title Page. AC and RP are physicians and academic professionals with internationally recognized expertise in the field of endocrinology and andrology; CdA, GG, MP MN and CP are biologists and biotechnologists employed as post-doctoral (GG, MP, MN) and researcher (CdA, CP); DM, FG and NV are physicians and currently Phd students; RSA and CS are physicians and researchers. The authors report there are no competing interests to declare; each author contributed to the preparation of this review as independent professional, and the review article preparation has not been supported financially. The authors received no specific funding for this work, and there are no contractual relations or proprietary considerations that restrict the author’s publication or dissemination of the findings described in the review article. None of the authors has participated in any legal, regulatory, or advocacy activities during the last 5 years, related to the contents of this article.