Testicular toxicity

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

Tricresyl phosphate (a complex mixture containing tri-o, Xn-m-, and tri-para-cresyl phosphate that is used in certain hydraulic fluids) and TOCP are demonstrated testicular toxicants in rodents (Carlton et al. 1987 Somkuti et al. 1987a, 1987b). Tricresyl phosphate also has been shown to impair in vivo fertility in rats and mice (Carlton et al. 1987 Chapin et al. 1988a). In addition, tricresyl phosphate-treated female rats displayed vacuolar cytoplasmic alteration of ovarian interstitial cells (Carlton et al. 1987 NTP 1994). Reproductive effects have also been seen after oral exposure to butylated triphenyl phosphate (Latendresse et al. 1994b). 

Chapin RE, Phelps JL, Somkuti SG, et al. 1990. The interaction of sertoli and leydig cells in the testicular toxicity of tri-ort/zo-cresyl phosphate. Toxicol Appl Pharmacol 104 483-495. 

Somkuti SG, Lapadula D, Chapin RM, et al. 1991. Light and electron microscopic evidence of tri-ortho-cresyl phosphate (TOCP)-mediated testicular toxicity in F344 rats. Toxicol Appl Pharmacol 107 35-46. 

Heywood, R. and James, R.W. (1985). Current laboratory approaches for assessing male reproductive toxicity Testicular toxicity in laboratory animals. In Reproductive Toxicology (Dixon, R.L., Ed.). Raven Press, New York, pp. 147-160. 

Dinitrobenzene is an intermediate employed in chemical syntheses of a large number of compounds used in the dye, explosives and plastics industry. The compound is known to induce methemoglobinemia and to cause testicular toxicity with the Sertoli cell being the major target. Nitro reduction was observed in erythrocytes, in rat Sertoli-germ cell cocultures and in rat testicular subcellular fractions, and it was shown that 3-nitrosonitrobenzene was formed that was considerably more toxic. Testicular toxicity was enhanced when the intracellular thiol levels were reduced by pretreatment with diethylmaleate. In turn, pretreatment with cysteamine or ascorbate reduced the toxicity of 1,3-dinitrobenzene and 3-nitrosonitrobenzene. 

Plasma hormones and enzymes of testicular origin were used as markers for evaluation of acute testicular toxicity in rats treated with 1,3-DNB. Lactate dehydrogenase isozyme C4 (LDH-C4) and ABP were both elevated after treatment with doses between 10 and 25 mg/kg of 1,3-DNB (Reader et al. 1991). Testosterone levels were reduced after treatment with 10 and 32 mg/kg of 1,3-DNB (Reader etal. 1991 Rehnberg et al. 1988). 

Different susceptibility among species to reproductive effects seems also related to the metabolism of 1,3-DNB. Rats were much more susceptible to adverse reproductive effects of 1,3-DNB than hamsters (McEuen and Miller 1991 Obasaju et al. 1991). This was correlated with the fact that blood levels of 1,3-DNB in the hamster reached only half those found in the rat and that blood levels of the metabolite 1,3-nitroaniline were higher in the rat (McEuen and Miller 1991). Furthermore, rats excreted more unconjugated and less phenolic metabolites than hamsters. Results from studies with rat Sertoli/germ cell cocultures suggest that reactive metabolic intermediates such as nitrosonitrobenzene and nitrophenylhydroxylamine may be responsible for the testicular toxicity of... 

Linder RE, Hess RA, Strader LF. 1986. Testicular toxicity and infertility in male rats treated with... 

Moore NP, Creasy DM, Gray TJB, et al. 1992. Urinary creatine profiles after administration of cell-specific testicular toxicants to the rat. Arch Toxicol 66 435-442. 

Reader SC, Shingles C, Stonard MD. 1991. Acute testicular toxicity of 1,3-dinitrobenzene and ethylene glycol monomethyl ether in the rat Evaluation of biochemical effect markers and hormonal responses. Fundam AppI Toxicol 16 61-70. 

Allyl chloride was fetotoxic to rats exposed during gestation to 300ppm, which also caused considerable maternal toxicity in the form of kidney and liver injury. It was a testicular toxicant in mice, causing decreased testes weight, reduced numbers of spermatids, and increased frequency of abnormal sperm after a single subcutaneous injection to male mice at one-fifth the LDso. ... 

Zhao M Testicular toxicity of allyl chloride. Eukuoka Acta Medica 88(3) 49-55, 1997... 

DBCP is a genotoxic in microbial and mammalian assays. The mechanism for DBCP-induced testicular toxicity may be related to direct DNA damage. Binding of DBCP metabolites to testicular cell DNA has been demonstrated. Alternatively, inhibition of sperm carbohydrate metabolism could also account for DBCP toxicity to epididymal sperm. 

Dostal LA, Chapin RE, Stefanski SA, et al Testicular toxicity and reduced Sertoli cell numbers in neonatal rats by di-(2-ethylhexyl) phthalate and the recovery of fertility as adults. Toxicol Appl Pharmacol 95 104—121, 1988... 

Toxicology. All isomers of dinitrobenzene (DNB) cause anoxia due to the formation of methemoglobin moderate exposure causes respiratory tract irritation, and chronic exposure results in anemia. Testicular toxicity has been reported in laboratory animals after ingestion of 7 -DNB. 

Obasaju ME, Katz DE, Miller MG Species differences in susceptibility to 1,3-dini-trobenzene-induced testicular toxicity and methemoglobinemia. Eundam Appl Toxicol 16 257-266, 1991... 

Foster PMD, Creasy DM, Eoster JR, et al Testicular toxicity of ethylene glycol monomethyl and monoethyl ethers in the rat. Toxicol Appl Pharmacol 69 385-399, 1983... 

Toxicology. Ethylene dibromide (EDB) is a severe mucous membrane, eye, and skin irritant. It is a testicular toxicant and causes liver and kidney damage it is carcinogenic in experimental animals. 

Formigli L, Scelsi R, Pogg P, et al Thallium-induced testicular toxicity in the rat. Environ Ret 40 531-539, 1986... 

Mishra VK, Srivastava MK, Raizada RB Testicular toxicity of thiram in rat Morphological and biochemical evaluations. Ind Health 31 59-67, 1993... 

Capsules/Tablets/Oral solution - Use ribavirin with caution in fertile men. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles. 

Sasaki J, Chapin R, Hall D, Breslin W, Moffit J, Saldutti L, Enright B, Seger M, Jarvi K, Hixon M, Mitchard T, Kim JH (2011) Incidence and nature of testicular toxicity findings in pharmaceutical development. Birth Defects Res B Dev Reprod Toxicol 92(6) 511-525. doi 10.1002/bdrb.20338... 

Acute oral toxicity studies do not contribute to the assessment of reproductive toxicity as they lack organ weight measurements and histopathology. In a way this is unfortunate because the study design itself, a single high dose followed by a 2-week observation period, might be suited for early detection and preliminary characterization of testicular toxicants. 

Ku, W.W. and R.E. Chapin. 1994. Mechanism of the testicular toxicity of boric acid in rats in vivo and in vitro studies. Environ. Health Perspec. 102(Suppl. 7) 99-105. 

The testicular toxicity of di(2-ethylhexyl) phthalate is described in Section 4.3. 

The involvement of testosterone in the testicular atrophy caused by di(2-ethyl-hexyl) phthalate was examined by co-administration of testosterone (1 mg/kg bw) subcutaneously with 2000 mg/kg bw di(2-ethylhexyl) phthalate [purity not specified] in groundnut oil to adult male Wistar rats for 15 days (Parmar et al., 1987). Administration of di(2-ethylhexyl) phthalate reduced the sperm count and also significantly increased the activity of y-GT, lactate dehydrogenase and P-glucuronidase and decreased the activity of sorbitol dehydrogenase and acid phosphatase. Co-adminis-tration of testosterone seemed to normalize the sperm count and the activity of testicular enz5mies. The role of testosterone in the testicular toxicity of di(2-ethylhexyl) phthalate has not been fully elucidated. Several reports refer to increased or decreased testosterone levels in plasma and testicular tissue. 

In one study using small groups of adult marmosets, oral exposure did not cause testicular toxicity at doses higher than those producing testicular effects in adult rats. 

The Sertoli cells in the testes appear to be the main target of the testicular toxicity. Proposed mechanistic h otheses relate to reduced testicular zinc levels, altered hormonal status, altered metabolic function and altered follicle-stimulating hormone reactivity. 

---