Pathogenesis of Male Reproductive Toxicity

Abstract

Toxicologic disturbance of male reproductive function can occur at many sites and produce a range of effects, some primary and some secondary to the initial insult. The challenge to the toxicological pathologist is to identify the primary site of damage and provide an insight into the pathogenesis of the morphologic lesion or functional deficit. Target sites include the testis, the epididymis, the mature sperm, and the hormonal regulatory system. Detection of effects at these varied sites requires the measurement of multiple endpoints only 1 of which is histopathology, but once identified, careful microscopic examination of the early changes in lesion development can provide essential information on the probable target cell and possible mechanisms of toxicity. Chemicals that affect different cell types or specific cellular functions generally elicit predictable patterns of pathological changes that can be readily recognized. Understanding the pathogenesis, the likely reversibility and the significance of reproductive tract lesions is aided by a sound knowledge of the physiology of the testis and epididymis and, in particular, an understanding of the timing of sperm production and transport.

Proliferative and Nonproliferative Lesions of the Rat and Mouse Male Reproductive System

“…This can occur through decreased testosterone production from the testis, decreased metabolism of testosterone to dihydrotestosterone (the major effective androgen for epididymal function) or androgen receptor blockade. Inhibitors of steroid biosynthesis, such as ketoconazole, will result in testicular changes as well as epididymal atrophy, but androgen receptor antagonists such as flutamide or inhibitors of 5a-reductase (which converts testosterone to dihydrotestosterone) cause epididymal atrophy in the absence of any discernable morphological effects on the testis (Creasy 1999). Segmental atrophy of the epididymis at the junction between the corpus and cauda is sometimes seen as a background finding in rodents and can also be a chemically induced change.…”

“…The early effects of androgen deficiency are recognized by degeneration of round spermatids and pachytene spermatocytes in stage VII/VIII tubules of rats (Hikim, Leung, and Swerdloff 1995;Russell et al 1990). Mitotically active spermatogonia are affected by cytotoxic agents such as busulfan and bleomycin; pachytene spermatocytes by 2-methoxymethanol and dinitropyrroles; round spermatids by ethylmethane sulfonate and methyl chloride; and elongating spermatids by boric acid and dibromoacetic acid (Creasy 2001;Creasy and Foster 2002). Degeneration of occasional stage VII pachytene spermatocytes has been noted in young, foodrestricted rats due to decreased testosterone (Rehm et al 2008).…”

“…Estrogen receptor a knockout (ERKO) mice develop tubular dilation with subsequent pressure atrophy and infertility at an age when seminiferous fluid starts to be secreted (Eddy et al 1996). Tubular dilation has also been described following administration of endothelin antagonists (Creasy 2001), the fungicide carbendazim (Nakai et al 1992), and a 5HT agonist, where the pathogenesis was considered to be due to reduction in fluid resorption caused by vasoconstriction of the blood vessels in the mediastinal plexus overlying the rete testis (Piner et al 2002).…”

“…They have been described following administration of the water-disinfecting chemical dibromoacetic acid in rats (Linder et al 1994(Linder et al , 1997 (Keeney et al 1988). The resulting androgen deficiency causes decreased size and weight of the accessory sex glands and epididymides, which are androgen-dependent tissues (Creasy 2001). There may also be hypertrophy of gonadotropin-secreting cells in the pituitary and Vol.…”

“…injection directly into the testis (which can occur because the rat is able to retract its testes into the abdominal cavity). (Creasy 2001). The vacuoles may be intracellular or intercellular and in both cases probably reflect a disturbance in fluid balance of the Sertoli cell.…”