Di-n-butyl Phthalate is Toxic to the Male Reproductive System and Its Toxicity is Enhanced by Thioacetamide Induced Liver Injury

Abstract

Abstract:The modifying effects of liver injury on male reproductive organ toxicity of di-n-butyl phthalate (DBP) were studied using male F344 rats. Seventy-two male animals, aged 10 weeks at the commencement, were divided into 8 groups of 9 rats each. Groups 1 to 4 were given 200 mg/kg bw of thioacetamide (TAA) intraperitoneally 3 times / week, while Groups 5 to 8 were injected with the PBS vehicle only. From 1 week after the start, groups 1 and 5, 2 and 6, and 3 and 7 were given daily 500, 125, 31.25 mg/kg bw of DBP, respectively (23 times) for 4 weeks, while groups 4 and 8 served as vehicle controls. As the result of our treatment, liver injury was induced in the animals, and the liver injury was confirmed by histopathological findings and serum transaminase levels at sacrifice. Enhancement of rat male reproductive organ toxicity of DBP under liver injury status was also seen. The relative organ weights of prostate, bilateral seminal vesicles, bilateral epididymides and bilateral testes, and the sperm number and motility rate were decreased. Also the sperm abnormality rate was increased under liver injury. Furthermore histopathological abnormality of the testis, such as absence of germ cells and the presence of Sertoli cells only was seen in the rats treated with TAA and high dose of DBP, however neither the serum nor testicular testosterone levels varied in the present study. The sperm number and relative weight of bilateral epididymides were decreased by TAA treatment only, unrelated to DBP treatment. These facts suggest that liver injury can not only enhance the rat male reproductive organ toxicity of DBP, but also induce such toxicity by itself. (J Toxicol Pathol 2004; 17: 177-185)

The overview of current evidence on the reproductive toxicity of dibutyl phthalate

“…Finally, a decreased sperm count was observed. At this dose, the nonreproductive organs weight did not change, as was observed in the rodents receiving a lower dose [19,21]. When given orally at a dose of 500 mg/kg bw/day, DBP caused subsequent toxic effects in rodents, which are described in detail in Table 1 [15,17,21,24].…”

“…Abnormal sperm count was doubled in the lower dose; however, the rabbits exposed to the higher dose had a decreased sperm count. In the rabbits treated with DBP at a dose of 400 mg/kg bw/day, the epididymal sperm count did not change whereas a lower dose (≥100 mg/kg bw/day) in rodents caused adverse effects on sperm production [15,18,19]. Administering DBP at a dose of 520 mg/kg bw resulted in a decreased progressive and mass sperm motility and live sperm percentage, along with a significant elevation of testicular malondialdehyde, and without changes in other testicular enzymes.…”

“…When given orally at a dose of 500 mg/kg bw/day, DBP caused subsequent toxic effects in rodents, which are described in detail in Table 1 [15,17,21,24]. However, Mitsuhashi et al [19] found no changes in the serum and testicular testosterone levels despite the use 500 mg/kg bw of DBP in rats. In the Wistar rats treated with DBP at a dose of 600 mg/kg bw/day (via gavage for 15 days), necrosis of the seminiferous tubules was observed [16].…”

“…The mice given 812 mg/kg bw/day of DBP via food for 13 weeks showed increased zinc concentrations in the testes [23]. Table 1 (16 studies: 11 on rats, 2 on rabbits, 2 on mice, 1 on monkeys) [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. The table is divided by animal species (rats, mice, rabbits, monkeys) and exposure time (shorttime exposure -up to 28 days: 12 studies, and sub-chronic exposure -up to 13 weeks: 4 studies).…”

“…Some authors have concluded that male reproductive toxicity occurs through mechanisms related to these corresponding with oxidative stress [16,20,21]. A higher dose in rats (31 mg/kg bw) caused testicular atrophy and increased sperm abnormalities [19]. The rodents treated with DBP doses of >100 mg/kg bw (rats) or 163 mg/kg bw (mice) had a reduced sperm count and quality, with abnormal morphology of the seminiferous tubules [18,19].…”