Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

• Published in: Critical reviews in toxicology Vol. 29; no. 2; pp. 169 - 261
• Main Authors: Cook, Jon C., Klinefelter, Gary R., Hardisty, Jerry F., Sharpe, Richard M., Foster, Paul M. D.
• Format: Journal Article
• Language: English
• Published: Colchester Informa UK Ltd 01.01.1999; Taylor & Francis; Informa Healthcare; Taylor & Francis Ltd
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Cell Transformation, Neoplastic; chemically induced Leydig cell tumors; Disease Models, Animal; Endocrine System - drug effects; Experimental genital and mammary tumors; human relevance of rodent Leydig cell tumors; Humans; interstitial cell; interstitial cell tumors; Leydig cell; Leydig Cell Tumor - etiology; Leydig Cell Tumor - physiopathology; Leydig cell tumors; Leydig Cells - cytology; Leydig Cells - drug effects; Luteinizing Hormone - pharmacology; Male; Medical sciences; Mutagenicity Tests; Rats; review; Testicular Neoplasms - etiology; Testicular Neoplasms - physiopathology; testis; Tumors; Xenobiotics - adverse effects; Chemical compound; Cytokine; Radiation; Rodentia; Review; Malignant tumor; Testicle; Carcinogenesis; Leydig cell; Carcinogen; Vertebrata; Mammalia; Animal; Hormonal regulation; Man animal extrapolation; Male genital diseases; Testicular diseases
• ISSN: 1040-8444; 1547-6898
• DOI: 10.1080/10408449991349203

Leydig cells (LCs) are the cells of the testis that have as their primary function the production of testosterone. LCs are a common target of compounds tested in rodent carcinogenicity bioassays. The number of reviews on Leydig cell tumors (LCTs) has increased in recent years because of its common occurrence in rodent bioassays and the importance in assessing the relevance of this tumor type to humans. To date, there have been no comprehensive reviews to identify all the compounds that have been shown to induce LCTs in rodents or has any review systematically evaluated the epidemiology data to determine whether humans were at increased risk for developing LCTs from exposure to these agents. This review attempts to fill these deficiences in the literature by comparing the cytology and ontogeny of the LC, as well as the endocrine and paracrine regulation of both normal and tumorigenic LCs. In addition, the pathology of LCTs in rodents and humans is compared, compounds that induce LC hyperplasia or tumors are enumerated, and the human relevance of chemical-induced LCTs is discussed. There are plausible mechanisms for the chemical induction of LCTs, as typified by agonists of estrogen, gonadotropin releasing hormone (GnRH), and dopamine receptors, androgen receptor antagonists, and inhibitors of 5a-reductase, testosterone biosynthesis, and aromatase. Most of these ultimately involve elevation in serum luteinizing hormone (LH) and/or LC responsiveness to LH as proximate mediators. It is expected that further work will uncover additional mechanisms by which LCTs may arise, especially the role of growth factors in modulating LC tumorigenesis. Regarding human relevance, the pathways for regulation of the hypothalamo-pituitary-testis (HPT) axis of rats and humans are similar, such that compounds that either decrease testosterone or estradiol levels or their recognition will increase LH levels. Hence, compounds that induce LCTs in rats by disruption of the HPT axis pose a risk to human health, except for possibly two classes of compounds (GnRH and dopamine agonists). Because GnRH and prolactin receptors are either not expressed or are expressed at very low levels in the testes in humans, the induction of LCTs in rats by GnRH and dopamine agonists would appear not to be relevant to humans; however, the potential relevance to humans of the remaining five pathways of LCT induction cannot be ruled out. Therefore, the central issue becomes what is the relative sensitivity between rat and human LCs in their response to increased LH levels; specifically, is the proliferative stimulus initiated by increased levels of LH attenuated, similar, or enhanced in human vs. rat LCs? There are several lines of evidence that suggest that human LCs are quantitatively less sensitive than rats in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. This evidence includes the following: (1) the human incidence of LCTs is much lower than in rodents even when corrected for detection bias; (2) several comparative differences exist between rat and human LCs that may contribute, at least in part, to the greater susceptibility of the rat to both spontaneous and xenobiotic-induced LCTs; (3) endocrine disease states in man (such as androgen-insensitivity syndrome and familial male precocious puberty) underscore the marked comparative differences that exist between rats and man in the responsiveness of their LC's to proliferative stimuli; and (4) several human epidemiology studies are available on a number of compounds that induce LCTs in rats (1,3-butadiene, cadmium, ethanol, lactose, lead, nicotine) that demonstrate no association between human exposure to these compounds and induction of LC hyperplasia or adenomas. After considering the human incidence of LCTs, the comparative differences between rats and humans, human endocrine disease states, and epidemiology, the weight of evidence suggests that human LCs are quantitatively less sensitive than rat LCs in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. It can be concluded that no observable effect levels for the induction of LCTs in rodent bioassays provide an adequate margin of safety for protection of human health and that the data support a nonlinear mode of action (i.e., threshold response). In conclusion, the data suggest that nongeno toxic compounds that induce LCTs in rats most likely have low relevance to humans under most exposure conditions because humans are quantitatively less sensitive than rats. In a recent international multidisciplinary workshop on LC tumorigenesis, seven research needs were identified. In this review, we have begun to address two of these needs (comparative sensitivity differences and epidemiology), and as the other areas of research are further investigated, these data will help to critically test the conclusions in this review.