摘要:

A dose-response study was conducted in a rat model to examine the effects of lifetime lead exposure on the development of the reproductive system and the endocrine mechanisms underlying these effects. Time-impregnated female Sprague-Dawley rats (n = 10-15/ group) were exposed to lead acetate in the drinking water at levels of 0.05%, 0.15%, or 0.45% (w/v) initiated on gestational day 5. At birth, litters were culled to four male and four female pups. Exposure of dams to lead was continued until weaning, following which, the pups continued to be exposed to lead acetate in drinking water until sacrifice. One male and one female pup from each litter were sacrificed at age 21, 35, 55, and 85 d. A significant dose-responsive decrease in birth weight and crown-to rump length was observed in all lead-exposed litters. However, no marked effects were observed on anogenital distance/crown-to-rump length ratios. Lead exposure resulted in a delay in sexual maturity as measured by prostate weight in male pups and time of vaginal opening in female pups, which increased with lead dose. These disruptions in reproductive physiology were accompanied by a significant decrease in neonatal sex steroid levels and suppression of the plasma concentrations of testosterone (male) and estradiol (female) during puberty. In male pups, this was accompanied by a significant decrease in plasma luteinizing hormone (LH), elevated pituitary LH content, and a decrease in plasma testosterone/LH ratios at the highest dose. In female pups, although no effects were observed on plasma LH concentration, a similar significant elevation in pituitary LH content was observed during early puberty. Postpuberty, plasma LH and sex steroid concentrations were unaffected at any dose in spite of continued lead exposure. No significant effects were observed on epididymal sperm count in male pups at 85 d of age. In female pups, estrus cycling was only significantly disrupted at the highest lead dose. These data suggest that the reproductive axis is particularly sensitive to lead during specific developmental periods, resulting in delayed sexual maturation pro duced by suppression by sex steroid biosynthesis. The mechanisms underlying this appear to involve lead actions on both LH release and gonadal function. At low, environmentally relevant blood lead concentrations, adaptation to the continuous presence of the metal ion occurs and surprisingly little effect is observed on adult reproductive endocrinology and physiology.

ISSN:1528-7394    

DOI:10.1080/009841098158935

出版商:Informa UK Ltd    

年代:1998

数据来源: Taylor

摘要:

A dose-response study was conducted to examine the growth suppression associated with developmental lead exposure in a rat model and to determine the endocrine mechanisms underlying these effects. Ad libitum intake of lead acetate (0.05% to 0.45% w/v) was initiated in time-impregnated female Sprague-Dawley rats (n = 10-15/ group) at gestational day 5. At birth, pups were culled to four male and four females per litter. Lead exposure of dams continued until weaning, following which lead exposure of pups was continued until sacrifice at age 21, 35, 55, and 85 days. Birth weight and prepubertal and pubertal growth rates were significantly suppressed. Growth rates were suppressed to a much greater degree in male as compared to female pups. Decreased growth rates were accompanied by a significant decrease in plasma insulin-like growth factor 1 (IGF1) concentrations and (1) a significant increase in pituitary growth hormone (GH) content during puberty in pups of both sexes, (2) a delay in the developmental profiles of the GH-dependent male-specific liver enzymes cytochrome P-450 CYP2C11 and N -hydroxy-2-acetylaminofluorene sulfotransferase, and (3) continued suppression of these enzymes in lead-exposed adult male pups. In addition, significant decreases in plasma sex steroids, testosterone (male) and 17 -estradiol (female), were observed during puberty. Postpuberty, at age 85 d, both IGF1 and sex steroid levels were indistinguishable from control pups despite continued lead exposure. Growth rates were also similar in control and lead-exposed pups between age 57 and 85 d. Data suggest that the mechanism underlying lead-induced sex-independent suppression of growth observed in these studies involves disruption of GH secretion during puberty. It is possible that the mechanisms underlying the greater suppression of somatic growth observed at puberty in lead-exposed male offspring may be due to the additional hypoandrogenization produced by the action of lead on the hypothalamic-pituitary-testicular axis.

ISSN:1528-7394    

DOI:10.1080/009841098158944

出版商:Informa UK Ltd    

年代:1998

数据来源: Taylor

摘要:

2-Methylimidazole (2-MI), widely used as a chemical intermediate, is also present in cigarette smoke and may form in food and forage as a result of ammoniation of simple sugars. 2-MI has been shown to be neurotoxic in several animal species and to alter serum levels of T3, T4, and thyroid-stimulating hormone (TSH) in the rat, apparently leading to hyperplasia of thyroid follicular cells. In order to better characterize 2-MIinduced toxicity, the disposition of \[2-14C]-2-MI has been investigated following po administration of either 5, 50, or 150 mg/kg to male F344 rats. Excretion data indicated that absorption of 2-MI was both rapid and proportional to dose in the range studied. Approximately 90% of the total dose was eliminated in urine within 24 h. Most of the remaining 14C was excreted in feces and as expired 14CO2. Excretion data were similar following iv administration of 5 mg/ kg. Little or no enterohepatic circulation of compound occurred, since biliary excretion of 2-MI-derived 14C was negligible. Approximately 70% of the 14C excreted in urine, following all dosing, consisted of parent compound. High-performance liquid chromatography (HPLC) chromatograms for all treatment groups were similar, indicating that metabolism of 2-MI in rats was not affected by dose or route of administration.

ISSN:1528-7394    

DOI:10.1080/009841098158953

出版商:Informa UK Ltd    

年代:1998

数据来源: Taylor

摘要:

Dolichols are long-chain polyprenols containing 14-22 isoprene units, present in mammalian tissues as free dolichol (Free-Dol), fatty acyl dolichyl esters (Dol-FA), and dolichyl phosphate (Dol-P). The hepatic level of Dol-P seems to be a rate-limiting factor for glycosylation processes. Previous studies from our laboratory demonstrated the susceptibility of the dolichol molecule to undergo radical attacks. Since the toxicity of 1,1,2,2-tetrachloroethane (TTCE)is dependent on the free-radical production during hepatic biotrasformation, it was of interest to determine whether this haloalkane might affect glycosylation mechanisms by changing dolichol levels and distribution in rat liver microsomes and Golgi apparatus (GA) . Male Sprague-Dawley rats received a single dose of TTCE (574 mg/kg body weight) and were then sacrificed at different times (5,15, 30, or 60 min). In the TTCE-treated rats both serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and hepatic triglycerides (TG) were significantly higher than control, while microsomal glucose 6-phosphatase (G6Pase) activity was decreased. In total microsomes Dol-P levels considered rate-limiting for the biosynthesis of the N -glycosylated proteins were significantly lower than in the control group 15 min after TTCE treatment. In normal rat liver, F secretory fraction of GA is 60-1 fold enriched in total dolichol content with respect to microsomes. In this compartment the total dolichol content, essential for the increase in membrane fluidity and permeability required for glycoprotein maturation and secretion, decreased significantly 5 min after TTCE treatment. Our results suggest that TTCE may affect dolichol functions in rat liver.

ISSN:1528-7394    

DOI:10.1080/009841098158962

出版商:Informa UK Ltd    

年代:1998

数据来源: Taylor

摘要:

Inhalation pharmacokinetics of the environmental contam inants 1,1,1-trichloroethane, tetrachloroethylene, trichloroethylene, benzene, and p -dichlorobenzene were determined in male Sprague-Dawley rats, and data generated were used to obtain fundamental data for risk assessment of chronic low-level exposures to these substances. Measured amounts of the substances were injected into a closed chamber system in which a rat had been placed, and the concentration changes in the chamber air were examined. The pharmacokinetics of the substances were evaluated using linear or nonlinear compartment models. The metabolic elimination amounts at various exposure concentrations were extrapolated using the estimated pharmacokinetic parameters. At low (1 ppb) concentration exposure to benzene or trichloroethylene the fraction of elimination of these substances was 1.6 and 1.5 times higher, respectively, than that seen at high (10 ppm) concentration exposure. Extrapolation kinetics of low-exposure data showed more trichloroethylene (0.0016 mumol/h/kg), benzene (0.0014 mumol/h/kg), and p -dichlorobenzene (0.00052 mumol/h/kg) was absorbed by the rats than 1,1,1- trichloroethane (0.000019 mumol/h/kg) and tetrachloroethylene (0.000029 mumol/h/kg). Although the exposure concentrations for all chemicals were equal, the differences in absorption quantities need to be considered in evaluation of potential risk assessment.

ISSN:1528-7394    

DOI:10.1080/009841098158971

出版商:Informa UK Ltd    

年代:1998

数据来源: Taylor

摘要:

Cadmium and chromium are both well-known human carcinogens, and common exposures to these metals are not infrequent. Recent studies have shown that hexavalent chromium induces apoptosis in Chinese hamster ovary (CHO) cells, suggesting an association of apoptosis with carcinogenesis. In contrast, induction of apoptosis by cadmium has been inconsistently observed. The present study was designed to determine if cadmium could induce apoptosis in CHO cells and if common exposure to cadmium and chromium would modify any apoptotic response. Apoptosis was evaluated by both agarose gel and in situ end-labeling methods. Apoptosis was observed at 48 h after treatment with 300 mu M chromium (Na2CrO4) for 2 h. Cadmium alone at concentrations of 1, 5, or 10 mu M (as CdCl2) did not induce apoptosis in these cells even at times up to 72 h after treatment. However, when CHO cells were concurrently exposed to cadmium and chromium, chromium-induced apoptosis was markedly suppressed in a cadmium concentration-related fashion. Cadmium did not consistently modify the cytotoxic effects of chromium, and significant increases in metallothionein were not induced by these metal treatments. These findings indicate that cadmium can block chromiuminduced apoptosis. The suppression of apoptosis by cadmium may be a significant aspect of its carcinogenic mechanism.

ISSN:1528-7394    

DOI:10.1080/009841098158980

出版商:Informa UK Ltd    

年代:1998

数据来源: Taylor