Testicular toxicity testis

Mehrotra et al. (1997, 1999) presented preliminary evidence for the involvement of the thyroid and the hypophysis in DEHP-induced testicular toxicity in rats. They reported that hypothyroidism or hypophysectomy prevented, to some extent, DEHP-induced alterations in several xenobiotic-metabolizing enzymes in the testis. The significance of these findings is unclear due to a lack of DEHP-induced decreased testicular weight in sham-operated controls, which complicates comparison to the hypophysectomized animals. 

Figure 12-1 Testicular toxicity in rats given a small molecule non-specific ACC inhibitor for 14 days. (A) Testis from control (B) Testis from treatment group. Note necrotic and degenerative round spermatids, including synctia (arrows), and reduced cellularity of seminiferous epithelium in several tubes.

Ejqrert Panel conclusions are summarized in Table 17.4.2. Since primates showed no testis effects when exposed to DEHP at oral doses similar to those which wonld cause testicular toxicity in juvenile rodents, the Expert Panel has a minimal concern that ambient human exposures adversely affect adult httman reproduction However, exposure of healthy infants and toddlers, whose reproductive systems are still developing, is more of concern. Thus, if an infant or toddler is ejqrosed to levels higher than that expected with ambient adult exposiue, the Expert Panel has concern that exposure may adversely affect male reproductive tract development. Because it is possible that exposures of critically ill male infants who are exposed via medical therapy can approach doses that are toxic in rodent models, the Expert Panel has serious concern that such exposure may adversely affect male reproductive tract development. Because oral exposure for humans is estimated at <30 tg/kg bw/day and toxic effects are observed in rodents at >3 mg/kg bw/day, the Expert Panel has concern that ambient oral DEHP exposures of pregnant or lactating women may adversely affect the development of their offspring. 

Many compounds have been implicated as male reproductive toxicants, but their sites and mechanisms of action are not well understood. The classification of male reproductive toxicants as direct or indirect is useful to help define the primary site of toxicity (Figure 6). A direct toxicant would primarily target the testicular cells, the excurrent duct system of the male reproductive tract, or mature spermatozoa. An indirect toxicant would cause reproductive toxicity by acting on hypothalamic/pituitary neuroendocrine controls or on extragonadal systems. Since the testis is subject to hormonal control and feedback loops, the action of indirect toxicants on endocrine homeostasis can ultimately damage testicular cell types. 

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