Rodent Leydig cell tumorigenesis: A review of the physiology, pathology, mechanisms, and relevance to humans

Leydig cells (LCs) are the cells of the testis that have as their primary f unction the production of testosterone. LCs are a common target of compound s tested in rodent carcinogenicity bioassays. The number of reviews on Leyd ig cell tumors (LCTs) has increased in recent years because of its common o ccurrence in rodent bioassays and the importance in assessing the relevance of this tumor type to humans. To date, there have been no comprehensive re views 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 e xposure 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 bath normal and tumorigenic LCs. In addition, the pathology of LCTs in rodents and humans is compared, comp ounds that induce LC hyperplasia or tumors are enumerated, and the human re levance of chemical-induced LCTs is discussed. There are plausible mechanisms for the chemical induction of LCTs, as typif ied by agonists of estrogen, gonadotropin releasing hormone (GnRH), and dop amine receptors, androgen receptor antagonists, and inhibitors of Sa-reduct ase, testosterone biosynthesis, and aromatase. Most of these ultimately inv olve elevation in serum luteinizing hormone (LH) and/or LC responsiveness t o LH as proximate mediators. It is expected that further work will uncover additional mechanisms by which LCTs may arise, especially the role of growt h factors in modulating LC tumorigenesis. Regarding human relevance, the pathways for regulation of the hypothalamo-p ituitary-testis (HPT) axis of rats and humans are similar, such that compou nds that either decrease testosterone or estradiol levels or their recognit ion will increase LH levels. Hence, compounds that induce LCTs in rats by d isruption of the HPT axis pose a risk to human health, except for possibly two classes of compounds (GnRH and dopamine agonists). Because GnRH and pro lactin receptors are either not expressed or are expressed at very low leve ls in the testes in humans, the induction of LCTs in rats by GnRH and dopam ine agonists would appear not to be relevant to humans; however, the potent ial relevance to humans of the remaining five pathways of LCT induction can not be ruled out. Therefore, the central issue becomes what is the relative sensitivity between rat and human LCs in their response to increased LH le vels; specifically, is the proliferative stimulus initiated by increased le vels of LH attenuated, similar, or enhanced in human vs. rat LCs? There are several lines of evidence that suggest that human LCs are quantit atively less sensitive than rats in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. This evidence inclu des the following: (1) the human incidence of LCTs is much lower than in ro dents even when corrected for detection bias; (2) several comparative diffe rences exist between rat and human LCs that may contribute, at least in par t, to the greater susceptibility of the rat to both spontaneous and xenobio tic-induced LCTs; (3) endocrine disease states in man (such as androgen-ins ensitivity syndrome and familial male precocious puberty) underscore the ma rked comparative differences that exist between rats and man in the respons iveness of their LC's to proliferative stimuli; and (4) several human epide miology studies are available on a number of compounds that induce LCTs in rats (1,3-butadiene, cadmium, ethanol, lactose, lead, nicotine) that demons trate no association between human exposure to these compounds and inductio n 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 sens itive than rat LCs in their proliferative response to LH, and hence in thei r sensitivity to chemically induced LCTs. It can be concluded that no obser vable effect levels for the induction of LCTs in rodent bioassays provide a n adequate margin of safety for protection of human health and that the dat a support a nonlinear mode of action (i.e., threshold response). In conclus ion, the data suggest that nongenotoxic compounds that induce LCTs in rats most likely have low relevance to humans under most exposure conditions bec ause humans are quantitatively less sensitive than rats. In a recent intern ational multidisciplinary workshop on LC tumorigenesis, seven research need s were identified. In this review, we have begun to address two of these ne eds (comparative sensitivity differences and epidemiology), and as the othe r areas of research are further investigated, these data will help to criti cally test the conclusions in this review.