Recent studies demonstrated that preadolescent male rats are more sensitive to testicular damage from exposure to DEHP than adults. Male and female marmosets were treated daily with 0, 100, 500, or 2500 mg/kg DEHP by oral gavage for 65 wk from weaning (3 mo of age) to sexual maturity (18 mo). No treatment-related changes were observed in male organ weights, and no microscopic changes were found in male gonads or secondary sex organs. Sperm head counts, zinc levels, glutathione levels, and testicular enzyme activities were comparable between groups. Electron microscopic examination revealed no treatment-related abnormalities in Leydig, Sertoli, or spermatogenic cells. Histochemical examination of the testis after 3beta-hydroxysteroid dehydrogenase (3beta-HSD) staining did not reveal any alterations in steroid synthesis in the Leydig cells. Thus, although marmoset monkeys were treated with 2500 mg/kg DEHP, throughout the pre- and periadolescent period, no histological changes were noted in the testes. For females, increased ovarian and uterine weights and elevated blood estradiol level were observed in higher dosage groups, 500 and 2500 mg/kg. These increased weights were associated with the presence of large corpus luteum, a common finding in older female marmosets. Although an effect on the female ovary cannot be completely ruled out, no abnormal histological changes were observed in the ovaries or uteri in comparison to controls. No increases in hepatic peroxisomal enzyme activities were noted in treated groups; isolated hepatic enzyme activities (P-450 contents, testosterone 6beta-hydroxylase, and lauric acid omega-1omega-hydroxylase activities) were increased in males and/or females of either the mid- or high-dose groups, but no consistent dose-related trend was observed.

To evaluate the toxicological effect, di(2-ethylhexyl)phthalate (DEHP) was administered orally at 100, 500, and 2500 mg/kg to four male and four female marmosets in each group for 13 weeks. Its potentials of hepatic peroxisome proliferation, testicular atrophy, and pancreatic acinar cell hyperplasia were evaluated more closely. Clofibrate, which potently causes peroxisome proliferation in rodents, was administered in like manner at 250 mg/kg as a reference drug. DEHP induced significant suppression of weight gain in males at 2500 mg/kg. However, the increase in liver mass and hypertrophy of hepatocytes were not detected in organ weight measurements or histopathological examination. The number of peroxisomes, volume density, peroxisome morphology, and peroxisomal enzyme activities were not different from those in the control group, though the males treated with 500 and 2500 mg/kg DEHP showed 1.3- and 1.4-fold increases in mean peroxisome volume, respectively. In contrast, clofibrate induced 2.2 (in male)- and 1.9-fold (in female) increases in hepatic cyanide-insensitive acyl CoA oxidation system activity, 1. 2 (in male)- and 1.7-fold (in female) increases in hepatic carnitine-dependent acetyltransferase activity, and 1.8 (in male)- and 3.0-fold (in female) increases of carnitine-dependent palmitoyltransferase activity. Cytochrome P-450 contents tended to increase in all males and females administered 500 and 2500 mg/kg of DEHP and clofibrate associated with the increase in hepatic microsomal protein content, suggesting a relationship with the treatment. The atrophic change in the testis or proliferative change in the pancreatic acinar cells seen in rodents were not seen histopathologically; also, no changes were observed in testes weight, testicular zinc level, blood levels of testosterone and estradiol, pancreas weight, and blood levels of cholecystokinin. Finally, no changes considered to be due to the administration of DEHP were noted in blood chemical examination or pathological examination of other organs.

-We compared the metabolic profile of di (2-ethylhexyl) phthalate (DEHP) in juveniles and fetus between rats and marmosets. STUDY-I: 14 C-DEHP (100 and 2,500 mg/kg) was singly administered to juvenile and adult marmosets by gavage. C max of the radioactivity in juvenile marmosets was 6.45 and 31 μg eq./g, respectively. The radioactivity excreted mainly into feces; however, at least 10% of the radioactivity was absorbed even at 2,500 mg/kg. No abnormal accumulation was observed in the male reproductive organs. STUDY-II: 14 C-DEHP (100 mg/kg) was singly administered to juveniles of rat and marmoset. The plasma radioactivity in marmosets was about 5% to 9% of that in rats. Free forms of mono-2-ethylhexyl phthalate (MEHP) and its oxidized metabolites such as oxo-, OH-, and COOH-MEHP were detected as the main compositions in rat plasma. In marmosets, free form of MEHP was also detected as a major composition, but not for oxidized MEHP metabolites. In rats, oxidized MEHP metabolites were excreted into urine as unconjugated forms. MEHP and its oxidized metabolites were also detected in marmoset urine; however, they were mostly glucuronized. No specific accumulation of the radioactivity was noted in the testes of either species; however, the radioactivity concentration in the marmoset testes was much lower than that in rats. STUDY-III: 14 C-DEHP (100 mg/kg) was singly administered to dams on gestation day 130 for marmosets and day 20 for rats. In either species, no specific accumulation of radioactivity was noted in the testis of fetuses from the dams treated with 14 C-DEHP; however, the radioactivity in the rat testis was about 20-times higher than that in the marmoset. Major metabolite components in rat whole fetal tissue were free forms of MEHP, OH-MEHP, and oxo-MEHP. Free form of MEHP was also detected as only a peak in the marmoset fetal tissue.