Effects of perinatal combined exposure to 1,1-dichloro-2,2 bis (p-chlorophenyl) ethylene and tributyltin on male reproductive system.

Prenatal or early postnatal exposure to some synthetic chemicals may affect the later reproductive system of the offspring. There may also be unique responses observed due to exposure to combinations of chemicals that are not observed when the chemicals are present individually. 1,1-Dichloro-2,2 bis (p-chlorophenyl) ethylene (p,p'-DDE) is a persistent metabolite of DDT and tributyltin (TBT) compounds are used primarily as antifouling agents, as they exert biocidal actions. p,p'-DDE and TBT are ubiquitously distributed in the environment. Oral p,p'-DDE and TBT intake through marine products is demonstrated to be high in Japan. Consequently, the foetus and neonate are supposed to be exposed much more to p,p'-DDE and TBT via the maternal body. Therefore, effects of perinatal exposure to p,p'-DDE and/or TBT on the reproductive system after maturation have been investigated in rat male offspring of dams orally administered 125 ppm p,p'-DDE (approximately 10 mg/kg) and 25 ppm TBT (approximately 2 mg/kg) during the gestational and lactational period. In this study, growth retardation attributed to TBT has sustained in rat male offspring after perinatal exposure. However, perinatal exposure to p,p'-DDE and TBT failed to affect the male reproductive organs and sperm parameters in matured male offspring.

Normal Development of Reproductive System in Rat Male Offspring Following Perinatal Combined Exposure to p,p'-DDE and 1,4-Dichlorobenzene.

Prenatal or early postnatal exposure to some synthetic chemicals may affect the later reproductive system of the offspring, and there may also be unique responses observed due to exposure to combinations of chemicals that are not observed when the chemicals are present individually. Organochlorine compounds are ubiquitously distributed in the environment. p,p'-DDE (1,1-dichloro-2,2 bis (p-chlorophenyl) ethylene) is a persistent metabolite of DDT and 1,4-dichlorobenzene (DCB) is used as an air freshener or a moth repellent. Oral p,p'-DDE intake through marine products and DCB concentrations of residential air are demonstrated to be high in Japan. Consequently, the fetus and neonate are supposed to be exposed much more to p,p'-DDE and DCB via the maternal body. Therefore, effects of perinatal combined exposure to p,p'-DDE and DCB on the male reproductive system after maturation have been investigated in rat male offspring of dams ingesting these contaminants during the perinatal period from gestational day 1 to postpartum day 21. In this study, no deteriorated developmental effects have been observed in rat male offspring until maturation following oral administration of 125 ppm p,p'-DDE (approximately 10 mg/kg) and 25 ppm DCB (approximately 2 mg/kg) to dams. Further, no obvious effects of perinatal combined exposure to DCB and p,p'-DDE on the male reproductive organs and sperm parameters were observed in mature male offspring.

Effects of concurrent exposure to tributyltin and 1,1-dichloro-2,2 bis (p-chlorophenyl) ethylene (p,p'-DDE) on immature male Wistar rats.

Tributyltin and 1, 1-dichloro-2, 2 bis (p-chlorophenyl) ethylene (p,p'-DDE) have been ubiquitously distributed over the world. In Japan, p,p'-DDE and tributyltin are ingested through marine products, in which these substances are accumulated through bio-concentration and the food chain. However, the consequence of potential combined hazards of these substances remains unknown. Therefore, the effects of concurrent exposure to 125 ppm p,p'-DDE and 25 ppm tributyltin were investigated in immature male Wistar rats by oral administration during puberty. In this study, tributyltin promoted the growth of pubertal male rats, while p,p'-DDE itself did not affect the growth but inhibited the growth enhancement by tributyltin. Furthermore, tributyltin reduced thymus weight but p,p'-DDE also prevented this weight reduction. Neither development of male sexual accessory organs nor sexual maturation was affected even by concurrent exposure to p,p'-DDE and tributyltin. No significant changes of serum testosterone, luteinizing hormone, follicle-stimulating hormone concentrations, and epididymal sperm numbers were observed with the administration of p,p'-DDE and/or tributyltin. These results indicate that sexual maturation, male reproductive organ development and sperm production is scarcely affected in immature male Wistar rats even by concurrent exposure to p,p'-DDE and tributyltin at a daily dose of ca. 2 mg/kg tributyltin and 10 mg/kg p,p'-DDE. Moreover, the simultaneous administration of p,p'-DDE with tributyltin counterbalanced the effects that were attributed to tributyltin alone.

The effects of subacute inhalation of di (2-ethylhexyl) phthalate (DEHP) on the testes of prepubertal Wistar rats.

In animal studies using oral dosing for short periods, di (2-ethylhexyl) phthalate (DEHP) is well known for its reproductive toxicity, especially for its testicular toxicity. However, extending the period of DEHP exposure in prepubertal rats resulted in significant increases in testosterone. This suggests that the reproductive effect of DEHP might be associated with the timing and the term of exposure. Moreover, the route of exposure may induce differences in its effect because tissue levels of metabolites of DEHP after inhalation are thought to be different from those after oral administration. We researched the effects of inhalation of DEHP on testes of prepubertal rats. Our results showed that inhalation of DEHP by 4-wk-old male Wistar rats at doses of 5 or 25 mg/m(3), 6 h per day, for 4 and 8 wk significantly increased the concentration of plasma testosterone and weight of seminal vesicles. However, the concentration of luteinizing hormone (LH), follicular stimulating hormone (FSH) and the expression of mRNAs of androgen biosynthesis enzyme, cytochrome P450 cholesterol side-chain-cleavage enzyme (P450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), cytochrome P450 17alpha-hydroxylase/17, 20 lyase (CYP17) and aromatase (CYP19) did not change. Rats with precocious testes did not increase in any of the DEHP groups. We also found that the estimated effective dose in this study was less than those reported in previous studies which used oral dosing. Our study showed that inhaled DEHP increased plasma testosterone concentrations in prepubertal rats and suggested that their effects were more sensitive to inhalation of DEHP than oral dosing.

A comprehensive evaluation of the testicular toxicity of dichlorvos in Wistar rats.

Assessments of the reproductive toxicity of organophosphorus insecticides are important public health issues. This study aimed at defining the testicular toxicity of dichlorvos (DDVP) since this toxicity was suspected by our previous survey on pesticide sprayers and in some earlier publications during the 1970s. Ten-week-old Wistar rats were divided into four groups (n=8 or 9) and were injected subcutaneously with DDVP (0, 1, 2 or 4 mg/kg) 6 days a week for 9 weeks. After that period, erythrocyte cholinesterase (ChE) activities decreased dose-dependently, showing 44-55% inhibition among the treated groups. No significant difference was observed in the reproductive organ weights in any treated groups compared with the control group. Sperm motility decreased slightly but significantly in the 1 and 4 mg/kg groups, and significant regressions were observed between sperm motility and both blood ChE activity and urinary concentration of dimethyl phosphate (DMP), a urine metabolite of DDVP. However, sperm counts and sperm morphology in the cauda epididymidis, plasma testosterone concentrations, and histopathology in the testes in all the treated groups were not significantly different from those of the control group. Since only the sperm motility deteriorated by DDVP exposure at doses inducing marked inhibition of cholinesterase activities in the rats, it was suggested that the risk of testicular dysfunction posed to occupationally exposed humans would be small in terms of the effect of DDVP exposure alone. This conclusion was also supported by an estimate of the decrease in human sperm motility based on the urinary DMP concentrations observed in actual occupational settings.

Fat-containing variant of solitary fibrous tumor (lipomatous hemangiopericytoma) arising on surface of kidney.

Fat-containing variant of a solitary fibrous tumor is a recently recognized benign soft-tissue tumor that usually affects the thigh and retroperitoneum. We report a 51-year-old woman with a fat-containing variant of a solitary fibrous tumor that is the first reported case involving a visceral organ. The tumor was well delineated and seemed to arise from the renal capsule, radiographically and macroscopically. The tumor microscopically mimicked a solitary fibrous tumor but exhibited focal aggregates of fat cells. A fat-containing variant of a solitary fibrous tumor involving the kidney should be distinguished from spindle cell carcinoma, angiomyolipoma, gastrointestinal stromal tumor, and cellular schwannoma.

Effects of perinatal simultaneous exposure to tributyltin (TBT) and p,p'-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene) on male offspring of Wistar rats.

p,p'-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene; DDE] and tributyltin (TBT) are ubiquitous in the environment and in Japan were shown to bioaccumulate in marine products. Thus these chemicals serve as a source of contaminant in the mammalian food chain. Fetuses and neonates through maternal ingestion may be exposed to DDE and TBT. Therefore, the effects of concurrent exposure to DDE and TBT were investigated in male Wistar rat offspring of dams ingesting these two contaminants. In this study, TBT suppressed the growth and delayed eye opening. However, both growth retardation and delayed eye opening produced by TBT failed to occur in the presence of DDE. Unexpectedly, the prostate weight of male rat offspring was significantly reduced with the administration of TBT but restored in the presence of DDE. These results indicate that TBT and DDE affected the development of male rat offspring following maternal exposure, and simultaneous administration of DDE prevented some of the observed effects of TBT, especially of an antagonistic nature, through a mechanism, still to be determined.

Distribution of tributyltin, dibutyltin and monobutyltin in the liver, brain and fat of rats: two-generation toxicity study of tributyltin chloride.

The distribution of tributyltin (TBT) and its metabolites, dibutyltin (DBT) and monobutyltin (MBT), was examined in the liver, brain and fat tissues in a two-generation reproductive toxicity study of tributyltin chloride (TBTCl) in rats using dietary supplementation at concentrations of 5, 25 and 125 ppm. In the liver, irrespective of TBTCl dietary concentration, gender or generation, the highest concentration of metabolite was consistently MBT, followed by DBT, and then TBT. In contrast, TBT was consistently present at the highest concentration in the brain, nearly always followed by DBT and MBT. In fat tissues, the concentrations of the three butyltin compounds showed similar relationships to those observed in the brain, although the concentrations were much lower. In the liver, the concentration of TBT was higher in females, and those of DBT and MBT were higher in males. Factorial ANOVA also suggested the effect of gender on the concentrations of the three butyltin compounds in the liver. The results of this study suggest tissue-dependent distribution of TBT, DBT and MBT and gender-dependent distribution of the three metabolites in the liver of rats.

Systemic effects of orally administered p, p'-DDE on immature male Wistar rats during pubertal period.

Systemic effects of p, p'-DDE (1, 1-dichloro-2, 2 bis (p-chlorophenyl) ethylene; DDE) on immature male rats were investigated in pubertal Wistar rats after oral administration of DDE. Special rat chow containing 125 ppm DDE (approximately 10 mg/kg DDE) had been administered daily for 42 d since 6 wk of age and its effects had been observed until 12 wk of age. The administration of DDE did not produce any overt signs of toxicity. Neither physical development nor sexual maturation was affected, and serum biochemistry was not impaired at the dose used in this experiment. Moreover, the male reproductive organs and epididymal sperm count were not affected by the administration of DDE during the pubertal period. Our results showed that even immature male rats were resistant to DDE exposure at the daily dose of ca. 10 mg/kg, but metabolic and immunological changes still remained uncertain. Further investigation should be conducted to reveal all the effects of DDE on immature male rats.

Effects of simultaneous administration of tributyltin (TBT) and p,p(')-DDE on female offspring of Wistar rats.

p,p(')-DDE (DDE) and tributyltin (TBT) occur globally and in Japan were shown to bioaccumulate in marine products, thus serving as a source of contamination in the mammalian food chain. Consequently, fetuses and neonates, through maternal ingestion, may be exposed to DDE and TBT. Therefore, the effects of combined DDE and TBT were investigated in female Wistar rat offspring of dams ingesting these two contaminants. In this study, TBT suppressed the growth of female offspring and delayed eye opening. However, both growth retardation and delayed eye opening produced by TBT failed to occur in the presence of DDE. These results indicated that TBT or DDE affected the development of female rat offspring following maternal exposure and simultaneous administration of DDE prevented some of the observed effects of TBT through a mechanism that remains to be elucidated.

Systemic toxicity of p,p'-DDE in aged male Wistar rats following oral administration.

Systemic toxicity of p,p'-DDE (DDE) in aged male rats was investigated in Wistar rats by oral administration of DDE. About 10 mg/kg DDE had been daily administered for 28 days from 48 weeks to 52 weeks of age and its effects were observed subsequently. The administration of DDE did not give rise to any overt signs of toxicity. Male reproductive organs were not affected and serum biochemistry was not impaired at the dose of this experiment. Organ weights of the liver and spleen slightly increased and the thymus weight reduced with DDE administration. Serum total cholesterol and free T4 levels slightly decreased with DDE administration, albeit statistically insignificant. Our results indicated that even aged male rats were resistant to DDE exposure at the daily dose of ca. 10 mg/kg. However, metabolic and immunological changes still remained uncertain. Further investigation should be performed to reveal the entire effects of DDE on aged male rats.

Low dose effects of bisphenol A on sexual differentiation of the brain and behavior in rats.

There is an endocrinological concern that environmental endocrine disrupters (EEDs) may influence sexual differentiation. Bisphenol A (BPA), one of EEDs, is released from polycarbonate plastics, and has been detected in the human umbilical cord. In this study, we examined the effect of BPA on the sexual differentiation of open-field behavior and the sexually dimorphic nuclei in the brain in the offspring of rats exposed to BPA during the fetal and suckling periods at a dosage below the human tolerable daily intake (TDI) level. In the control group, females were more active in the open field and had a larger locus coeruleus (LC) volume than males. BPA abolished and inverted the sex differences of the open-field behavior and the LC volume, respectively, without affecting the reproductive system. We also compared the effects of estrogenic compounds, diethylstilbestrol (DES) and resveratrol (RVT), to that of BPA because of their structural similarities. DES affected the open-field behavior, LC volume and reproductive system, while RVT affected the LC volume and the reproductive system. These results suggest that the brain is highly sensitive to BPA at a dosage below TDI and that the disrupting effects of BPA on sexual differentiation may vary from those of RVT and DES.

Testicular toxicity evaluation of two antimony compounds, antimony trioxide and antimony potassium tartrate, in rats and mice.

OBJECTIVES: Testicular toxicities of antimony compounds were evaluated in rats and mice. The slightly water-soluble antimony compound antimony trioxide (ATO) and the highly water-soluble antimony compound antimony potassium tartrate (APT) were examined. METHODS: Daily doses of the compounds were 27.4, 12.0 and 1,200 mg/kg body weight in the APT group, low-ATO group and high-ATO group, respectively. The corresponding daily doses of antimony were 10, 10 and 1,000 mg/kg body weight, in the APT group, low-ATO group and high-ATO group, respectively. Both compounds were administered by gavage: rats, 3 days per week for 4 weeks; mice, 5 days per week for 4 weeks. RESULTS: Neither compound reduced the weights of reproductive organs or accessory sex organs nor affected sperm parameters. Few marked histopathologic changes were found in the testes of the treated animals. Even at 1,200 mg/kg body weight, which is greater than the LD(50) of APT, ATO produced no effects. CONCLUSIONS: In this study, it was found that ATO and APT are not toxic to testes in rodents.