Male adolescent exposure to endocrine-disrupting pesticides: vinclozolin exposure in peripubertal rabbits

Abstract

Adolescence is a time of dramatic neuroendocrine changes that are required for sexual maturation. Hormonal mimicking or inhibiting chemicals can cause significant impairment during this critical period. Vinclozolin (Vin) has been shown to be an anti-androgen affecting male offspring in rats in utero, and its mechanism of action may be mediated by inhibition of androgenic receptor action. The majority of teenagers working on farms are male, and therefore a systemic fungicide, vinclozolin, was selected for study. The rabbit has proved to be an excellent species for modelling reproductive toxicant effects in the male and was selected as the test species. The peripubertal phase for the rabbit was determined to be between the 3rd and 4th months. A 2-month dosing period was therefore initiated at 3 months of age and carried through to the 4th month. Vin was administered by dermal application (100 mg kg(-1) in 100 microl of dimethylsulphoxide) daily. Body weights were determined weekly. The rabbits were then held until fully mature (6 months of age). Semen was collected and evaluated from sexually mature males on a weekly schedule for 5 weeks to maximize sperm output. An automated solid phase extraction procedure for monitoring exposures through isolation and quantification of Vin and its metabolic products was developed. Increased plasma levels of Vin and M2 were found throughout the experimental period. The exposed rabbits had a smaller weight gain during pubertal growth (approaching significance; P=0.059). At maturity, the accessory sex glands of the exposed animals weighed less than those of the controls (P=0.016). Surprisingly, the pooled sperm count of the exposed animals was significantly higher (P=0.017) than that of the unexposed animals. The anti-androgenic effects of Vin may have blocked the negative feedback mechanism of testosterone on the hypothalamus or pituitary gland, allowing for an increase in gonadotrophin release, and consequently increasing sperm production at puberty.

Reproductive Disorders in Pubertal and Adult Phase of the Male Rats Exposed to Vinclozolin during Puberty

“…Decreases in accessory sex organ weights including epididymis, prostate, and seminal vesicle by VCZ or FLU treatment were in agreement with those in other studies reported previously [1,[7][8][9]. In general, treatments of an antiandrogen induce a microscopic alteration in the testis of rats, commonly characterized by hypertrophy of Leydig cells [1,7].…”

“…These results in the present study indicate that the treatment of antiandrogen for ten consecutive days during puberty in male rats could affect sperm counts of cauda epididymis in adulthood. Moorman et al [8] reported a controversial result that showed an increased count of pooled sperms in the rabbit. The reason for the discrepancy is unclear.…”

“…An exposure of VCZ from weaning to early adult stage in male rats delayed preputial separation and pubertal onset, and reduced weights of androgen-dependent tissues including the ventral prostate, seminal vesicles and epididymis [7]. Peripubertal treatment of VCZ to male rabbits decreased accessory sex organ weights but increased pooled sperm counts [8]. However, there are no available reports related to reproductive disorders in male rats treated with VCZ during puberty.…”

Disruption of sexual function, FSH secretion, and spermiogenesis in rabbits following developmental exposure to vinclozolin, a fungicide

“…The potential problem is that hydrolytic products 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1) and especially 3 0 ,5 0 -dichloro-2-hydroxy-2-methylbut-3-enanilide (M2) effectively compete with endogenous androgens for androgen receptor (K i vs R1181 (methyltrienolone) of more than 700, 92 and 9.7 mM for vinclozolin, M1 and M2; Kelce et al 1994), and block the desired response. Both M1 and M2 are formed in rats and rabbits , Moorman et al 2000, and accumulate in soil, plants, and animals. There is a paucity of information on human exposure to metabolites of vinclozolin.…”

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Vinclozolin

“…With respect to effects on spermatogenesis, there is a report demonstrating a decrease in the number of sperm in F1 male rats due to maternal administration of vinclozolin at high doses of 100 mg/kg and above Gray et al, 1994). On the other hand, an increase in the number of sperm due to administration of vinclozolin to rabbits during sexual maturation has also been reported (Moorman et al, 2000). The blood concentrations of LH, FSH, testosterone, and DHT rose to nearly the same extent in F0 and F1 males in this study.…”