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BIOCHEMICAL AND MOLECULAR CHANGES AT THE CELLULAR LEVEL IN RESPONSE TO EXPOSURE TO ENVIRONMENTAL ESTROGEN-LIKE CHEMICALS |
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Journal of Toxicology and Environmental Health,
Volume 50,
Issue 1,
1997,
Page 1-30
Deodutta Roy, Murali Palangat, Chiao-Wen Chen, Ronald D. Thomas, John Colerangle, Alfonzo Atkinson, Zhi-Jie Yan,
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摘要:
Estrogen-like chemicals are unique compared to nonestrogenic xenobiotics, because in addition to their chemical properties, the estrogenic property of these compounds allows them to act like sex hormones. Whether weak or strong, the estrogenic response of a chemical, if not overcome, will add extra estrogenic burden to the system. At elevated doses, natural estrogens and environmental estrogen-like chemicals are known to produce adverse effects. The source of extra or elevated concentration of estrogen could be either endogenous or exogenous. The potential of exposure for humans and animals to environmental estrogen-like chemicals is high. Only a limited number of estrogen-like compounds, such as diethylstilbestrol (DES), bisphenol A, nonylphenol, polychlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (DDT), have been used to assess the biochemical and molecular changes at the cellular level. Among them, DES is the most extensively studied estrogen-like chemical, and therefore this article is focused mainly on DES-related observations. In addition to estrogenic effects, environmental estrogen-like chemicals produce multiple and multitype genetic and/or nongenetic hits. Exposure of Syrian hamsters to stilbene estrogen (DES) produces several changes in the nuclei of target organ for carcinogenesis (kidney): (1) Products of nuclear redox reactions of DES modify transcription regulating proteins and DNA; (2) transcription is inhibited; (3) tyrosine phosphorylation of nuclear proteins, including RNA polymerase II, p53, and nuclear insulin-like growth factor-I receptor, is altered; and (4) DNA repair gene DNA polymerase transcripts are decreased and mutated. Exposure of Noble rats to DES also produces several changes in the mammary gland: proliferative activity is drastically altered; the cell cycle of mammary epithelial cells is perturbed; telomeric length is attenuated; etc. It appears that some other estrogenic compounds, such as bisphenol A and nonylphenol, may also follow a similar pattern of effects to DES, because we have recently shown that these compounds alter cell cycle kinetics, produce telomeric associations, and produce chromosomal aberrations. Like DES, bisphenol A after metabolic activation is capable of binding to DNA. However, it should be noted that a particular or multitype hit(s) will depend upon the nature of the environmental estrogen-like chemical. The role of individual attack leading to a particular change is not clear at this stage. Consequences of these multitypes of attack on the nuclei of cells could be (1) nuclear toxicity/cell death; (2) repair of all the hits and then acting as normal cells; or (3) sustaining most of the hits and acting as unstable cells. Proliferation of the last type of cell is expected to result in transformed cells.
ISSN:0098-4108
DOI:10.1080/009841097160573
出版商:Informa UK Ltd
年代:1997
数据来源: Taylor
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2. |
LEAD-INDUCED CHANGES IN OVARIAN FOLLICULAR DEVELOPMENT AND MATURATION IN MICE |
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Journal of Toxicology and Environmental Health,
Volume 50,
Issue 1,
1997,
Page 31-40
Mohammad Junaid, D. K. Chowdhuri, R. Narayan R. Shanker D. K. Saxena,
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摘要:
Lead, a potent reproductive toxicant in humans and experimental animals, was used to detect the morphological basis of ovarian toxicity in mice by counting the various stages of follicular development using different doses of lead acetate (0, 2, 4 or 8 mg/kg/d) for 60 d (5 d/wk) by oral gavage. Our results revealed that while small and medium follicles were significantly affected even at the lowest dose (2 mg), the large follicles were affected mostly at the highest dose. Atresia even in the medium follicles reflected the extent of damage caused by lead. These findings correlated well with increased blood lead levels. Therefore, lead seems to affect the follicular development and maturation, if mice are exposed to sufficiently high concentrations of metal through the oral route.
ISSN:0098-4108
DOI:10.1080/009841097160582
出版商:Informa UK Ltd
年代:1997
数据来源: Taylor
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3. |
KETONE POTENTIATION OF INTRAHEPATIC CHOLESTASIS: EFFECT OF TWO ALIPHATIC ISOMERS |
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Journal of Toxicology and Environmental Health,
Volume 50,
Issue 1,
1997,
Page 41-52
Alexandra B. Duguay and Gabriel L. Plaa,
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摘要:
Occupational exposure to methyl isobutyl ketone (MiBK) or methyl n-butyl ketone (MnBK) normally occurs by inhalation. The present study reports that exposure to both ketones can potentiate cholestasis experimentally induced by taurolithocholic acid (TLC, 30 mol/kg) or by a combination of manganese (Mn, 4.5 mg/kg) and bilirubin (BR, 25 mg/kg). Male Sprague-Dawley rats were exposed for 3 d, 4 h/d, to MiBK or MnBK vapors using 0.5, 1, 1.5, or 2 times the minimal effective concentration (MEC). The estimated MiBK or MnBK MEC for potentiating TLC- or Mn-BR-induced cholestasis were 400 and 150 ppm, respectively. Eighteen hours after ketone exposure, rats were injected iv with TLC or Mn-BR. Bile flow was measured from 15 to 150 min after the cholestatic regimen. Rats exposed to MiBK or MnBK exhibited an enhanced diminution in bile flow compared to controls that was dose-dependent with the inhaled ketone dose. The dose-effect characteristics of the potentiation phenomenon were established. Results indicate that MiBK or MnBK inhalation potentiated both TLC and Mn-BR cholestasis in a dose-related fashion. Quantitative differences, however, exist between both ketones with respect to their ability to potentiate both models. Comparison between the two isomers was established, and MnBK was found to be more potent than MiBK.
ISSN:0098-4108
DOI:10.1080/009841097160591
出版商:Informa UK Ltd
年代:1997
数据来源: Taylor
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4. |
EFFECTS OF BENZOTHIOPHENE ON MALE RATS FOLLOWING SHORT-TERM ORAL EXPOSURE |
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Journal of Toxicology and Environmental Health,
Volume 50,
Issue 1,
1997,
Page 53-66
Raymond Poon, Hugh Davis, Pierre Lecavalier, Robert Liteplo, Al Yagminas, Ih Chu Craig Bihun,
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摘要:
The systemic toxicity of benzothiophene, a sulfur-containing heterocyclic present in petroleum, coal, and their derived products, was studied in male rats following short-term oral exposure. Male Sprague-Dawley rats (130 20 g) (n = 5 per dose group) were treated with benzothiophene by gavage at dosages of 0, 2, 20 or 200 mg/kg/d for 21 d. In another study, male rats were treated with 0, 100, or 500 ppm benzothiophene via the diet for 28 d. In the gavage study, the 200 mg/kg/d rats showed depressed weight gain, increased relative liver and kidney weights, decreased relative thymus weights, and elevated levels of serum-glutamyltransferase (-GT), hepatic aniline hydroxylase (AH), aminopyrine N-demethylase (APDM), pentoxyresorufin O-dealkylase (PROD), glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UDPGT) activities. A 4.5-fold increase in urine volume on d 14-21 and a transient, 4-fold increase in urinary ascorbic acid on d 1 were also detected. No treatment related changes in urinary N-acetylglucosaminidase (NAGA) activity were observed. Benzothiophene residues were not detected in adipose tissue, liver, and serum of rats in the 200 mg/kg rats, but a small quantity was detected in the urine. In the diet study, animals fed the 500 ppm diet had increased absolute and relative liver weights, elevated AH, APDM, and GST activities, decreased red blood cell count, and minor increases in serum urea nitrogen and glucose. In summary, benzothiophene produced adverse effects in male rats that included increased relative liver and kidney weights and increased urine output. Benzothiophene also caused increases in hepatic drug metabolizing enzyme activities of a phenobarbital type and a transient elevation in urinary ascorbic acid.
ISSN:0098-4108
DOI:10.1080/009841097160609
出版商:Informa UK Ltd
年代:1997
数据来源: Taylor
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5. |
INGESTION OF CHROMIUM(VI) IN DRINKING WATER BY HUMAN VOLUNTEERS: ABSORPTION, DISTRIBUTION, AND EXCRETION OF SINGLE AND REPEATED DOSES |
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Journal of Toxicology and Environmental Health,
Volume 50,
Issue 1,
1997,
Page 67-95
B. D. Kerger B. L. Finley G. E. Corbett, D. G. Dodge D. J. Paustenbach,
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摘要:
This study examines the magnitude of hexavalent chromium [Cr(VI)] absorption, distribution, and excretion following oral exposure to 5 and 10 mg Cr(VI)/L in drinking water administered as a single bolus dose (0.5 L swallowed in 2 min) or for 3 d at a dosage of 1 L/d (3 doses of 0.33 L each day, at 6-h intervals). Adult male volunteers ingested deionized water containing various concentrations of potassium chromate, and samples of urine, plasma, and red blood cells (RBCs) were collected and analyzed for total chromium throughout the studies. In the bolus dose studies, a fairly consistent pattern of urinary chromium excretion was observed, with an average half life of about 39 h. However, 4-d total urinary chromium excretion and peak concentrations in urine and blood varied considerably among the 5 volunteers. Studies of repeated exposure to smaller volumes ingested at a more gradual rate (i.e., 0.33 L over 5-15 min) showed similar urinary chromium excretion patterns but generally lower chromium uptake/excretion. Given that sustained elevations in RBC chromium levels provide a specific indication of chromium absorption in the hexavalent state, these data suggest that virtually all (>99.7%) of the ingested Cr(VI) at 5 and 10 mg Cr(VI)/L was reduced to Cr(III) before entering the bloodstream. The interindividual differences in total chromium uptake and excretion are plausibly explained by ingestion of appreciable doses on an empty stomach, which likely results in the formation of well-absorbed Cr(III) organic complexes in gastrointestinal tissues and possibly the blood. The lack of any clinical indications of toxicity in the volunteers and the patterns of blood uptake and urinary excretion of chromium are consistent with a predominant uptake of Cr(III) organic complexes [derived from Cr(VI)]that are excreted more slowly than inorganic forms of Cr(III). Therefore, it appears that the endogenous reducing agents within the upper gastrointestinal tract and the blood provide sufficient reducing potential to prevent any substantial systemic uptake of Cr(VI) following drinking-water exposures at 5-10 mg Cr(VI)/L. Based on these data, the chemical environment in the gastrointestinal tract and the blood is effective even under relative fasting conditions in reducing Cr(VI) to one or more forms of Cr(III).
ISSN:0098-4108
DOI:10.1080/009841097160618
出版商:Informa UK Ltd
年代:1997
数据来源: Taylor
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