Reproductive toxicity of triethylene glycol and its diacetate and dimethyl ether derivatives in a continuous breeding protocol in Swiss CD-1 mice.

Triethylene glycol and two of its derivatives were evaluated for reproductive toxicity in a continuous breeding protocol with Swiss CD-1 mice. Triethylene glycol (TEG: 0, 0.3, 1.5, and 3%), triethylene glycol diacetate (TGD: 0, 0.75, 1.5, and 3%), and triethylene glycol dimethyl ether (TGDME: 0, 0.25, 0.5, and 1%) were administered in drinking water to breeding pairs (20 pairs per treatment group, 40 control pairs) during a 98-day cohabitation period. Reproductive function was assessed by the number of litters per pair, live pups per litter, proportion of pups born alive, and pup weight. There were no apparent effects on reproductive function in the animals receiving TEG or TGD at doses up to 3% in the drinking water (representing 6.78 or 5.45 g/kg, respectively). However, some developmental toxicity was demonstrated for both TEG and TGD. Continuous exposure of dams to 1.5 or 3% TEG significantly reduced live pup weight at birth compared to control and 0.3% TEG, while exposure to 3% TGD during lactation significantly (but reversibly) reduced pup body weights on Postnatal Days 14 and 21. In contrast, TGDME was toxic to the reproductive system as evidenced by decreases at the highest dose (1% TGDME; 1.47 g/kg) in the proportion of pairs that produced at least one litter, live pups per litter, and proportion of pups born alive, with dose-related trends seen in the latter two parameters. A crossover mating trial showed that TGDME was more toxic to the female than the male reproductive system. These data indicate that TGDME (1.47 g/kg) is a reproductive toxicant in Swiss mice while reproductive toxicity was not demonstrated in mice receiving TEG or TGD (at doses up to 6.78 or 5.45 g/kg, respectively).

Reproductive toxicity of sulfamethazine in Swiss CD-1 mice during continuous breeding.

Sulfamethazine (SMZ) was evaluated for reproductive toxicity in Swiss CD-1 mice using a continuous breeding protocol. SMZ was administered in the diet at 0, 0.25, 0.5, or 1% (w/w), which represented an average daily intake of 0, 313, 625, or 1250 mg SMZ/kg/day, respectively. Exposure of F0 male and female mice to 1% SMZ for 126 days resulted in a significant decrease in the mean number of live pups per litter and the number of litters produced (task 2); the percentage pups born alive to 1% SMZ females showed a nonsignificant decrease versus control females. The effects on fertility were rapid to onset (1 to 4 weeks) and cumulative in nature. F0 male and female body weights were slightly depressed from 3 weeks to the end of the study. The crossover mating trial (task 3) revealed that the adverse effect on fertility involved both treated partners in that litter size decreased when either 1% SMZ males were bred to control females or 1% SMZ females were mated with control males. After approximately 155 days of exposure of F0 mice to 1% SMZ, the terminal body weight of 1% SMZ females was significantly decreased and that of 1% SMZ males showed a nonsignificant decrease. In addition, the liver weight to body weight ratio of the males was increased. Further, the prostate and seminal vesicle weight to body weight ratios were decreased in 1% SMZ males relative to control males. No treatment-related gross or histopathological lesions were noted for the pituitary or reproductive organs of either sex. Sperm assessment indicated no significant difference in the epididymal sperm concentration or percentage motile or abnormal sperm.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproductive toxicity evaluation of acetaminophen in Swiss CD-1 mice using a continuous breeding protocol.

Acetaminophen (APAP) was evaluated for reproductive toxicity in Swiss CD-1 mice using a continuous breeding protocol. APAP was administered in the diet at 0, 0.25, 0.5, and 1.0% (w/w), which represented average daily intakes of 0, 357, 715, and 1430 mg APAP/kg/day, respectively. Exposure of parental (P) breeding pairs to 1% APAP in the diet for 14 weeks during cohabitation significantly decreased the number of litters per pair, and reduced, although not significantly, the number of live pups per litter. Importantly, 6 of 19 high-dose P pairs failed to produce a fifth litter, and this fully accounted for the diminished number of litters in this group. In addition, the fifth litter that was produced by the 13 high-dose P pairs averaged only about 9 live pups per litter, which correspondingly reduced the overall group average for this parameter. In comparison, the control and two lower-dose P pairs produced 11 or 12 live pups per litter on average. Although the birth weights for F1 pups in the final litter were unaffected by prenatal APAP exposure, postnatal growth was adversely affected as evidenced by retarded weight gain as measured at 28 and 74 +/- 10 days of age for all three dietary levels. At 1% APAP this weight gain effect was more pronounced at Day 28 than at Day 74 +/- 10, suggesting that nursing pups may have been exposed to higher concentrations or may be more sensitive to APAP and/or an active metabolite than were the young adults.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of ethylene glycol monobutyl and monophenyl ether reproductive toxicity using a continuous breeding protocol in Swiss CD-1 mice.

A continuous breeding reproduction study design was utilized to examine the reproductive toxicity of ethylene glycol monobutyl ether (EGBE) and ethylene glycol monophenyl ether (EGPE). Swiss CD-1 mice were administered EGBE in drinking water (0, 0.5, 1.0, and 2.0%, i.e., 0.7, 1.3, and 2.1 g/kg body wt/day) and EGPE was administered via the feed (0, 0.25, 1.25, and 2.5%, i.e., 0, 0.4, 2.0, and 4 g/kg body wt/day). Both male and female mice were dosed for 7 days prior to and during a 98-day cohabitation period. EGBE was toxic at the high (2%) and mid dose (1%) to adult F0 female mice: 13 out of 22 females at the high dose and 6 out of 20 at the mid dose died during the cohabitation period. Both the high- and mid-dose animals produced fewer litters/pair, fewer pups/litter, with decreased pup weight. These effects occurred in the presence of decreased body weight, decreased water consumption, and increased kidney weight. A crossover mating trial indicated that the reproductive effects could be attributed primarily to an effect on the female. This was substantiated at necropsy where testes and epididymis weights were normal as were sperm number and motility. Fertility of the offspring of the 0.5% group was normal in the presence of increased liver weights. With respect to EGPE, there was no change in the ability to produce five litters during the continuous breeding period. There was, however, a significant but small (10-15%) decrease in the number of pups/litter and in pup weight in the high-dose group. A crossover mating trial suggested a female component of the reproductive toxicity of EGPE. While fertility was only minimally compromised, severe neonatal toxicity was observed. By Day 21 there were only 8 out of 40 litters in the mid- and high-dose groups which had at least one male and female/litter. Second generation reproductive performance of the mid-dose group (1.25%) was unaffected except for a small decrease in live pup weight. In summary the reproductive toxicity of EGBE and EGPE was only evident in the female and occurred at doses which elicited general toxicity. EGBE was particularly toxic to adult female mice while EGPE was particularly toxic to immature mice of both sexes.

Reproductive effects of four phthalic acid esters in the mouse.

These studies compared the reproductive toxicity of four phthalates by a continuous breeding protocol. Mice were given diets with diethyl phthalate (DEP) (0.0, 0.25, 1.25, or 2.5%), di-n-butyl phthalate (DBP) (0.0, 0.03, 0.3, or 1.0%), di-n-hexyl phthalate (DHP) (0.0, 0.3, 0.6, or 1.2%), or di(2-ethylhexyl) phthalate (DEHP) (0.0, 0.01, 0.1, or 0.3%). Both male and female CD-1 mice were dosed for 7 days prior to and during a 98-day cohabitation period. Reproductive function was evaluated during the cohabitation period by measuring the numbers of litters per pair and of live pups per litter, pup weight, and offspring survival. There was no apparent effect on reproductive function in the animals exposed to DEP, despite significant effects on body weight gain and liver weight. DBP exposure resulted in a reduction in the numbers of litters per pair and of live pups per litter and in the proportion of pups born alive at the 1.0% amount, but not at lower dose levels. A crossover mating trial demonstrated that female mice, but not males, were affected by DBP, as shown by significant decreases in the percentage of fertile pairs, the number of live pups per litter, the proportion of pups born alive, and live pup weight. DHP in the diet resulted in dose-related adverse effects on the numbers of litters per pair and of live pups per litter and proportion of pups born alive at 0.3, 0.6, and 1.2% DHP in the diet. A crossover mating study demonstrated that both sexes were affected. DEHP (at 0.1 and 0.3%) caused dose-dependent decreases in fertility and in the number and the proportion of pups born alive. A crossover mating trial showed that both sexes were affected by exposure to DEHP. These data demonstrate the ability of the continuous breeding protocol to discriminate the qualitative and quantitative reproductive effects of the more and less active congeners as well as the large differences in reproductive toxicity attributable to subtle changes in the alkyl substitution of phthalate esters.

Photosensitive stages in pubertal development of male deer mice (Peromyscus maniculatus).

Male deer mice (Peromyscus maniculatus bairdii) were exposed to a long (15L:9D) or short (6L:18D) photoperiod during four stages of development. At 6 weeks of postnatal age degree of pubertal development was determined by measurement of testis and seminal vesicle weights and area of the androgen-dependent sebaceous gland. Continuous exposure to a short photoperiod beginning before conception (i.e. mother kept in short days), at conception, or at birth markedly retarded pubertal development. Initiation of short-day treatment after weaning at 3 weeks of age was partly effective in inhibiting puberty. Males exposed to long days beginning at weaning were stimulated fully, however, having reproductive organs as large at 6 weeks of age as those of males housed on long days for the entire experiment. These results indicate that pubertal development in male deer mice is regulated by early postnatal, but not prenatal, photoperiod. However, early after weaning, males are more responsive to increasing than to decreasing photoperiod.

Effect of transitional photoperiods on testicular development and puberty in male deer mice (Peromyscus maniculatus).

In a series of five experiments, young male deer mice (Peromyscus maniculatus bairdii) were exposed to photoperiods ranging in length from 3 to 19 h per 24-h period, as well as to constant light and constant darkness. Reproductive organ growth as measured at 6 weeks of age was inhibited by less than or equal to 11.5 h of light. In males receiving 11.5-19 h of light, there was a quantitative increase in reproductive organ size as a function of photoperiod. Rather than a 'critical' photoperiod partitioning reproductive inhibition and stimulation, there was a zone of gradual transition from inhibition to full stimulation. Histological analysis of testes demonstrated that spermatogenesis was stimulated by long photoperiods. Examination of the epidermal surface of the penis by scanning electron microscopy indicated that penile spine development was also regulated by photoperiod.

Evaluation of heart malformations in B6C3F1 mouse fetuses induced by in utero exposure to methyl chloride.

C57BL/6 female mice impregnated by C3H males mice to produce B6C3F1 fetuses were exposed daily for six hr to atmospheres containing 0, 250, 500, or 750 ppm methyl chloride, from gestation day 6 to gestation day 18. There were 74 to 77 females with copulation plugs per exposure concentration. Females exposed to 750 ppm ethyl chloride exhibited ataxia commencing on the seventh day of exposure (gestation day 12). They also showed hypersensitivity to touch or sound, tremors and convulsions. Six females in the 750 ppm group died and one was euthanized in extremis prior to scheduled sacrifice. On gestation day 18, all other females were euthanized for evaluation. Only dams exposed to 750 ppm exhibited significant decrease in body weight by gestation day 18, weight gain during the gestation period, and absolute weight gain (weight gain minus gravid uterine weight) versus controls. There were no treatment related-effects on these parameters in the other exposure groups. None of the groups exhibited exposure-related differences in pregnancy rate, gravid uterine weight, or maternal liver weight. There were no differences in the numbers of implantations, resorption, dead fetuses, nonlive (dead plus resorbed) fetuses, live fetuses, sex-ratio, or mean fetal body weight per litter. There was a significant exposure-related increase in the number and percentage of affected (nonlive plus malformed) fetuses per litter with the incidence of affected fetuses in the 750 ppm group significantly higher than controls. There was a statistically significant increase in the incidence of heart defects in the 500 and 750 ppm group relative to controls. Of the 37 fetuses in the study with heart defects, 23 were females, 14 were males. The heart defects observed included: absent or abnormal tricuspid valve, reduced number of papillary muscles and/or chordae tendineae on the right side, small right ventricle, globular heart, and white spots in the left ventricular wall. Multiple malformations were observed in one fetus from the 500 ppm group and in three fetuses in the 750 ppm group. It is concluded that methyl chloride inhalation exposure to pregnant C57BL/6 mice from gestation day 6 through gestation day 17 resulted in maternal toxicity only at the 750 ppm exposure concentration and was teratogenic to B6C3F1 conceptuses at exposure concentrations of 750 and 500 ppm, leading to fetal heart malformations. No evidence of embryo or fetotoxicity other than teratogenicity was seen at any of the exposure concentrations employed. No maternal, embryo or fetotoxicity or teratogenicity was associated with exposure of mice, during critical periods of embryo and fetal development, to 250 ppm of methyl chloride.

Social stimulation of reproductive development in male deer mice housed on a short-day photoperiod.

Male deer mice (Peromyscus maniculatus), born of mothers housed on a long-day (LD) photoperiod (15:9 hr light/dark), were either switched to a short-day (SD) photoperiod (6:18 hr) at birth or continued on their prenatal LD photoperiod. From weaning until 6 wk of age, the males were housed either in cohabitation with an adult female or in social isolation. Males reared on an SD photoperiod had smaller testes, seminal vesicles, and ventral sebaceous glands than did males reared on LD. Postweaning exposure of SD meals to females stimulated reproductive organ growth as measured at 6 wk of age. Both photic and social stimuli regulate reproductive development in male deer mice. Positive social cues can stimulate maturation even in the presence of negative photic cues.