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1.
Regul Toxicol Pharmacol ; 69(3): 348-70, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24813373

ABSTRACT

Endocrine-related endpoints in animals have been reported to respond to high doses of methyl tertiary-butyl ether (MTBE), however, a systematic and transparent evaluation of endocrine potential has not been published. Resolving whether MTBE exhibits endocrine activity is important given regulatory and public interest in endocrine disrupting substances and their potential for causing adverse effects in humans or wildlife. A weight-of-evidence (WoE) analysis was conducted, focusing on hypotheses related to the potential for MTBE to interact with estrogen, androgen, and thyroid pathways, and steroidogenesis. To reach scientifically justified conclusions based on the totality of evidence, this WoE procedure involved a semi-quantitative relevance weighting of each endpoint for each hypothesis and systematic consideration of each endpoint in various study designs. This procedure maximized use of an extensive body of relevant and reliable literature on MTBE with evidence supporting or opposing a given mode of action hypothesis. Evaluating the strength and consistency of observations from many MTBE studies also provided a way to assess whether high doses used in experiments with MTBE confound identification of direct endocrine system responses. Based on results of studies using mammalian and fish models and in vitro screening assays, this WoE assessment reveals that MTBE lacks direct endocrine activity.


Subject(s)
Endocrine Disruptors/adverse effects , Endocrine System/drug effects , Methyl Ethers/adverse effects , Androgens/metabolism , Animals , Estrogens/metabolism , Humans , Thyroid Gland/drug effects
2.
Toxicology ; 319: 23-37, 2014 May 07.
Article in English | MEDLINE | ID: mdl-24560773

ABSTRACT

Methyl tertiary-butyl ether (MTBE) is a solvent and fuel additive included in reformulated gasoline to increase combustion efficiency. While widespread use in motor fuels in the U.S. was discontinued after MTBE was detected in surface and ground waters due to concerns about environmental persistence and water quality, it is still manufactured in the U.S. for export. Questions concerning the etiology of rat Leydig cell and mouse liver tumors identified in extremely high dose cancer studies have led to an interest in evaluating potential hormonal imbalances and endocrine system involvement. To address the possibility that MTBE or its metabolite, tert-butanol (TBA), are interacting with components of the endocrine system that are involved in steroidogenesis a number of targeted experiments were performed focusing mostly on the primary gonadal steroids, estradiol and testosterone. The goal of the experiments was to gain a better understanding of potential interactions with the steroidogenic pathway, including effects specifically on aromatase, the P450 enzyme that converts testosterone to estradiol. In three GLP-compliant in vitro guideline studies, MTBE and TBA were classified as non-binders to the androgen receptor, were classified negative for effects on testosterone and estradiol in the steroidogenesis assay, and were classified as non-inhibitors of aromatase activity. In three 14-day in vivo experiments involving gavaging of male Sprague-Dawley rats with doses of MTBE ranging from 400 to 1,500 mg/kg bw/day, the lack of definitive and consistent supporting statistically significant findings in steroid hormone measurements and aromatase activity and mRNA measured in liver and testis microsomes further suggested that it is unlikely that MTBE is interacting with the endocrine system directly. Evidence of other underlying systemic effects were also seen, including reduced body weight gain, increased adrenal weights, and elevated corticosterone suggestive of a more general stress response. Taken together, the results from these studies suggest that MTBE and TBA do not directly impact the steroidogenic pathways involved in estrogen and androgen production.


Subject(s)
Methyl Ethers/toxicity , tert-Butyl Alcohol/toxicity , Animals , Aromatase/genetics , Aromatase/metabolism , Corticosterone/blood , Estradiol/metabolism , Liver/drug effects , Liver/metabolism , Male , Rats , Rats, Sprague-Dawley , Receptors, Androgen/metabolism , Testis/drug effects , Testis/metabolism , Testosterone/metabolism
3.
Birth Defects Res B Dev Reprod Toxicol ; 89(3): 239-63, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20544807

ABSTRACT

Ethyl t-butyl ether (ETBE) is a motor fuel oxygenate used in reformulated gasoline. Knowledge of developmental and reproductive toxicity potential of ETBE is critical for making informed decisions about acceptance and regulations. This review discusses toxicology studies providing information about effects on reproduction and the conceptus. Seven GLP-compliant studies following widely accepted protocols have focused specifically on developmental and reproductive toxicity (DART) in rats and rabbits exposed to ETBE by gavage with doses up to 1,000 mg/kg body weight/day, the limit specified in standardized test guidelines. Other repeat-dose general toxicology studies have administered ETBE to rodents for up to 180 days, and included reproductive organ weights, histology, or other indications of reproductive system structure or function. DART potential of the main ETBE metabolite t-butyl alcohol and class-related MTBE has also been studied. More GLP-compliant studies exist for evaluating ETBE using well-established, currently recommended protocols than are available for many other chemicals used today. The database for determining ETBE DART potential is adequate, although not all study details are currently easily accessible for peer-review. ETBE does not appear to be selectively toxic to reproduction or embryofetal development in the absence of other manifestations of general toxicity. Studies using recommended methods for sample preservation and analysis have shown no targeted effect on the reproductive system. No embryofetal effects were observed in rabbits. Early postnatal rat pup deaths show no clear dose-response and have largely been attributed to total litter losses with accompanying evidence of maternal neglect or frank maternal morbidity.


Subject(s)
Embryonic Development/drug effects , Ethyl Ethers/toxicity , Reproduction/drug effects , Animals , Female , Fetus/drug effects , Methyl Ethers/toxicity , tert-Butyl Alcohol/toxicity
4.
Toxicol Lett ; 190(1): 74-80, 2009 Oct 08.
Article in English | MEDLINE | ID: mdl-19595749

ABSTRACT

These experiments were conducted to follow up on a report of testis seminiferous tubular degeneration in Fischer 344 rats treated with high doses of ethyl t-butyl ether (ETBE). Also, high doses of a related compound, methyl t-butyl ether (MTBE), had been shown to reduce circulating testosterone (T) in rats. Isolated rat Leydig cells were used to compare hCG-stimulated T production following exposure to ETBE, MTBE, and their common main metabolite, TBA. In addition, male Fischer 344 rats were gavaged daily with 600 mg/kg, 1200 mg/kg or 1800 mg/kg ETBE in corn oil (n=12) for 14 days, the 1200 mg/kg dose chosen for comparison with a prior 14-day MTBE gavage experiment. In cell culture experiments, TBA was more potent than either ETBE or MTBE, both of which caused similar inhibition of T production at equimolar concentrations. In the in vivo study, no significant plasma T reduction was seen 1h after the final 1200 mg/kg ETBE dose, whereas 1200 mg/kg MTBE had significantly lowered T when administered similarly to Sprague-Dawley rats. Some rats treated with 1800 mg/kg ETBE had noticeably lower T levels, and the group average T level was 66% of corn oil vehicle control (p>0.05) with high variability also evident in ETBE-treated rats. 17beta-Estradiol had been increased by 1200 mg/kg MTBE, and was elevated in the 1200 and 1800 mg/kg ETBE dose groups (p<0.05), both groups also experiencing significantly reduced body weight gain. None of these effects were seen with 600 mg/kg/day ETBE. No definitive evidence of androgen insufficiency was seen in accessory organ weights, and no testicular pathology was observed after 14 days in a small subset of 1800 mg/kg ETBE-treated animals. Like MTBE, ETBE appears to be capable of altering reproductive steroid levels in peripheral blood sampled 1h after treatment, but only with extremely high doses that inhibit body weight gain and may produce mortality.


Subject(s)
Air Pollutants/toxicity , Estradiol/blood , Ethyl Ethers/toxicity , Leydig Cells/drug effects , Testosterone/blood , Air Pollutants/metabolism , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Ethyl Ethers/metabolism , Leydig Cells/metabolism , Male , Methyl Ethers/metabolism , Methyl Ethers/toxicity , Organ Size/drug effects , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Reproduction/drug effects
5.
Reprod Toxicol ; 26(3-4): 246-53, 2008.
Article in English | MEDLINE | ID: mdl-18824092

ABSTRACT

MTBE is found in water supplies used for drinking and other purposes. These experiments follow up on earlier reports of reproductive tract alterations in male mice exposed orally to MTBE and explored oxidative stress as a mode of action. CD-1 mice were gavaged with 400-2000 mg/kg MTBE on days 1, 3, and 5, injected i.p. with hCG (2.5 IU/g) on day 6, and necropsied on day 7. No effect was seen in testis histology or testosterone levels. Using a similar dosing protocol, others had initially reported disruption of seminiferous tubules in MTBE-gavaged mice, although later conclusions published were consistent with our findings. Another group had also reported testicular and other reproductive system abnormalities in male BALB/c mice exposed for 28 days to 80-8000 microg/ml MTBE in drinking water. We gave these MTBE concentrations to adult mice for 28 days and juvenile mice for 51 days through PND 77. Evidence of oxidative stress was examined in liver homogenates from the juvenile study using MDA, TEAC and 8OH2hG as endpoints. MTBE exposures at the levels examined indicated no significant changes in the male mouse reproductive tract and no signs of hepatic oxidative stress. This appears to be the first oral MTBE exposure of juvenile animals, and also the first to examine potential for MTBE to cause oxidative stress in vivo using a typical route of human exposure.


Subject(s)
Genitalia, Male/drug effects , Liver/drug effects , Methyl Ethers/toxicity , Oxidative Stress/drug effects , Animals , Body Weight/drug effects , Lipid Peroxidation , Liver/metabolism , Male , Mice , Mice, Inbred BALB C , Organ Size/drug effects
6.
Regul Toxicol Pharmacol ; 47(2): 156-65, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17084497

ABSTRACT

There are no reports of studies that evaluate if methyl tertiary-butyl ether (MTBE) exposure causes cancer in humans. This evaluation of MTBE carcinogenicity is based on the results of animal studies. A weak tumorigenic response was reported for both MTBE and TBA in one tumor type (kidney) in male rats, for MTBE in one other tumor type (testicular) in male rats, for MTBE in one tumor type (liver) in female mice, and for TBA in one tumor type (thyroid) in female mice. The weight of the evidence does not support a genotoxic mode of action (MOA). Non-genotoxic MOAs have been demonstrated or suggested that correspond to the weak tumorigenic responses. These MOAs either do not occur in humans or humans are much less susceptible to these effects. It is, therefore, unlikely that humans would be exposed to sufficient levels of MTBE to cause these tumorigenic responses.


Subject(s)
Carcinogens/toxicity , Methyl Ethers/toxicity , Animals , Carcinogenicity Tests , Carcinogens/administration & dosage , Endpoint Determination , Female , Humans , Male , Methyl Ethers/administration & dosage , Mice , Mutagenicity Tests , Neoplasms/chemically induced , Predictive Value of Tests , Rats , Sex Factors , Species Specificity
7.
Article in English | MEDLINE | ID: mdl-16496297

ABSTRACT

BACKGROUND: Fetal uptake of an antisense oligonucleotide was evaluated after intravenous (i.v.) dosing of ISIS 2105, a 20-base phosphorothioate oligonucleotide, in timed-pregnant Sprague-Dawley rats. METHODS: To maximize the potential for fetal exposure, ISIS 2105 was administered as a 3-hr infusion at 6.6 mg/kg/hr with a total dose of 20 mg/kg, or as a continuous 7-day infusion at 0.35 mg/kg/hr with a total dose of 59 mg/kg. This dosing regime is higher than a patient would be expected to receive in the clinical use of oligonucleotides. Infusions were delivered through a jugular vein cannula by syringe pump on gestation day (GD) 19 (3-hr exposure) or by osmotic pumps implanted subcutaneously (s.c.) starting on GD 12 (7-day exposures). RESULTS: After a 3-hr infusion, maternal and fetal plasma concentrations of ISIS 2105 were >100 microg/ml and <0.07 microg/ml, respectively with a maternal fetal ratio of >1,000. Maternal regions of the placenta had twice the oligonucleotide concentration compared to fetal regions of the placenta (6 microg/g vs. 3 microg/g). After this acute exposure the concentrations in fetal kidney and liver were approximately 140- and 500-fold less than the maternal kidney and liver respectively. After 7-day infusion maternal plasma concentrations were 0.82 microg/ml and fetal concentrations were <0.22 microg/ml. By capillary gel electrophoresis (CGE) only the fetal liver consistently had quantifiable oligonucleotide concentrations (range=1.01-4.95 microg/g) compared to a mean concentration of 50.11+/-1.71 microg/g in the maternal liver a maternal to fetal ratio of approximately 10:50 after 7 days of infusion. CONCLUSIONS: There was a low level of transfer from dam to fetus, consistent with a slow equilibrium but the permeability of placenta to this 6 kDa polyanionic compound seemed to be limited even at supraclinical doses.


Subject(s)
Maternal-Fetal Exchange/physiology , Thionucleotides/administration & dosage , Thionucleotides/pharmacokinetics , Animals , Female , Infusions, Intravenous , Oligonucleotides/administration & dosage , Oligonucleotides/blood , Oligonucleotides/pharmacokinetics , Placenta/metabolism , Pregnancy , Rats , Rats, Sprague-Dawley , Thionucleotides/blood , Tissue Distribution
8.
Article in English | MEDLINE | ID: mdl-16290046

ABSTRACT

An American alligator (Alligator mississippiensis) breeding facility using male and female alligators raised from artificially incubated eggs was established in 1975. These alligators first reproduced at 6 years of age as compared to 10-12 years in wild alligators, but the eggs produced showed a lower hatching rate than those collected from the wild. By age 21 reproduction had failed almost completely. The alligators were sacrificed and tissues collected at necropsy from 44 captive and 15 wild animals and assayed for metals. Results showed that captive alligators had significantly higher tissue levels of lead than wild alligators. Cadmium did not differ between wild and captive and selenium was 50% higher in wild than captive alligator kidneys. Bone lead in captive alligators was 252,443 +/- 20,462 ng/g. High yolk lead was suggested as a probable cause for early embryonic death in alligator eggs. The high tissue lead levels in captive alligators was attributed to long-term consumption of nutria (Myocastor coypus) meat contaminated with lead shot. Liver, ovary, and testis were assayed for lipid peroxidation using the thiobarbituric acid (TBA) test. Captive alligators had 3.6 fold increased TBA-reactive materials in the liver tissue compared to wild. Lipid peroxidation was strongly suspected as having been enhanced by consumption of rancid nutria meat containing lead.


Subject(s)
Alligators and Crocodiles/physiology , Lead Poisoning/veterinary , Lead/analysis , Reproduction/drug effects , Animals , Animals, Domestic/physiology , Animals, Wild , Bone and Bones/chemistry , Cadmium/analysis , Diet/adverse effects , Egg Yolk/chemistry , Female , Gastrointestinal Contents/chemistry , Lipid Peroxidation , Liver/chemistry , Male , Ovary/chemistry , Rodentia , Selenium/analysis , Testis/chemistry , Thiobarbituric Acid Reactive Substances/analysis
9.
Public Health Nurs ; 22(5): 439-44, 2005.
Article in English | MEDLINE | ID: mdl-16229737

ABSTRACT

Nurses are often the first members of the healthcare system to whom the public turns when environmental health hazards cause concern. Yet most nursing programs include scant formal environmental health content. This article describes a project that integrated significant environmental health content into an undergraduate community health nursing course. The revised course included additional environmental health classroom content and field experiences. Details are provided regarding changes to classroom content, revision of written assignments to include environmental health issues, planning and implementation of nursing student field experiences with environmental health professionals, and evaluations of the revised course. The article concludes with three recommendations to guide other schools of nursing, wishing to integrate environmental health into their curricula.


Subject(s)
Community Health Nursing/education , Environmental Health/education , Curriculum , Humans , Program Development , Public Health Nursing , United States
10.
Nurse Educ ; 30(3): 104-8, 2005.
Article in English | MEDLINE | ID: mdl-15900202

ABSTRACT

The Environmental Health Risk Appraisal instrument simultaneously teaches students observational techniques of home visiting and environmental health risk assessment skills. Used in a community health nursing course, the authors describe how the instrument was integrated into clinical experiences and a comprehensive family analysis written assignment.


Subject(s)
Community Health Nursing/methods , Environmental Health , House Calls , Nursing Assessment/methods , Risk Assessment/methods , Surveys and Questionnaires/standards , California , Clinical Competence , Community Health Nursing/education , Curriculum , Education, Nursing, Baccalaureate , Family Health , Housing/standards , Humans , Medical History Taking/methods , Nursing Assessment/standards , Nursing Evaluation Research , Physical Examination/methods , Physical Examination/nursing , Risk Assessment/standards
11.
Cancer Lett ; 222(1): 119-24, 2005 May 10.
Article in English | MEDLINE | ID: mdl-15837549

ABSTRACT

Human mammary carcinoma MCF-7 cell line responsiveness to the pteridines xanthopterin and isoxanthopterin was studied using the MTS assay for measurement of cell viability. The pteridines were tested at concentrations ranging from 7.8 to 500 microM singly and in 11 isoxanthopterin:xanthopterin ratios. IC50s of xanthopterin and isoxanthopterin were 109+/-13 microM (mean+/-SEM of y estimate) and 103+/-9 microM, respectively. The IC50 values for pteridine mixtures were similar although 3:1 and 4:1 isoxanthopterin:xanthopterin ratios seemed slightly more cytotoxic than other mixtures. However, ANOVA revealed no statistical differences in the cytotoxicity of mixtures.


Subject(s)
Cell Survival/drug effects , Xanthopterin/pharmacology , Antineoplastic Agents/pharmacology , Breast Neoplasms , Cell Line, Tumor , Drug Combinations , Drug Synergism , Humans , Inhibitory Concentration 50 , Xanthopterin/toxicity
12.
Ecotoxicol Environ Saf ; 58(1): 90-5, 2004 May.
Article in English | MEDLINE | ID: mdl-15087168

ABSTRACT

Numerous reports have demonstrated the vitellogenic response of fish exposed to estrogenic compounds in the aquatic environment. A strong correlation has been shown to exist between plasma vitellogenin and plasma calcium concentrations in salmonid fish. This study examines the relationship between plasma vitellogenin and calcium in a cyprinid fish, the fathead minnow (Pimephales promelas), which is a species commonly used to monitor water quality. Plasma vitellogenin was determined after exposure of male and female fish to proprietary pharmaceutical estrogens using an enzyme-linked immunosorbent assay (ELISA) developed specifically for fathead minnows. Plasma calcium was determined by flame atomic absorption spectroscopy (AA). This study demonstrated significant (P < 0.05) linear correlations between plasma vitellogenin and plasma calcium for males (r2 = 0.70), females (r2 = 0.83), and males and females combined (r2 = 0.06), showing that plasma calcium could be an indirect measure of vitellogenin present in fathead minnows. Some of the limitations and advantages identified through these studies are discussed.


Subject(s)
Biomarkers/analysis , Calcium/analysis , Cyprinidae/physiology , Vitellogenins/analysis , Water Pollutants/toxicity , Animals , Endocrine System/drug effects , Estrogens/pharmacology , Female
13.
Oligonucleotides ; 14(4): 299-310, 2004.
Article in English | MEDLINE | ID: mdl-15665597

ABSTRACT

The effects of renal injury on the urinary excretion and tissue distribution of a 20-mer phosphorothioate oligonucleotide were investigated in male Sprague-Dawley rats. Renal injury was produced by treating the rats with either 5.0 mg/kg cisplatin or 2.5 mg/kg of a monoclonal antibody (mAb) directed toward Thy1.1. Controls received saline. Three days after cisplatin treatment or 2 days after anti- Thy1.1 treatment, the rats received 10 mg/kg ISIS 3521. Blood was collected at various times to assess the plasma concentrations of ISIS 3521, and rats were killed at various times from 6 to 48 hours after intravenous (i.v.) infusion of oligonucleotide to assess tissue concentrations by capillary gel electrophoresis (CGE). Cisplatin and anti-Thy1.1 antibody produced histologic and biochemical changes consistent with proximal tubular damage and glomerular damage, respectively. Urinary excretion of oligonucleotides was increased 2- to 4-fold of control; however, this amount accounted for only 1% to 2% of dose compared to 0.5% in controls. Proximal tubular damage reduced renal accumulations of ISIS 3521 and other oligonucleotide metabolites, but there were no obvious compensatory increases in concentrations in other organs except for a slight increase in spleen levels of total oligonucleotide. Glomerular damage was not associated with any change in oligonucleotide disposition. Immunohistochemical studies showed no evidence of alterations in the pattern of distribution within the injured kidney. The data suggest that acute renal dysfunction, either renal tubular or glomerular, does not markedly alter the urinary elimination and tissue deposition of a phosphorothioate oligonucleotide.


Subject(s)
Kidney Glomerulus/drug effects , Kidney Tubules/drug effects , Oligodeoxyribonucleotides, Antisense/pharmacokinetics , Thionucleotides/pharmacokinetics , Animals , Immunohistochemistry , Kidney Glomerulus/injuries , Kidney Glomerulus/pathology , Kidney Tubules/injuries , Kidney Tubules/pathology , Male , Oligodeoxyribonucleotides, Antisense/blood , Oligodeoxyribonucleotides, Antisense/pharmacology , Oligodeoxyribonucleotides, Antisense/urine , Organ Specificity , Rats , Rats, Sprague-Dawley , Thionucleotides/blood , Thionucleotides/pharmacology , Thionucleotides/urine , Time Factors
14.
Toxicol Sci ; 75(1): 208-22, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12832660

ABSTRACT

The use of in vitro systems to predict in vivo responses to chemical agents provides the benefits of requiring fewer animals, reducing variability between samples, requiring less test material, and enabling higher throughput. In the present study rat tissue slices and primary hepatocytes were compared as in vitro systems to predict in vivo changes in gene expression in response to treatment with known liver toxicants or inducers. Five compounds (phenobarbital, carbon tetrachloride, Wy-14,634, alpha-napthylisothiocyanate, and tacrine) were chosen for their established and diverse mechanisms of hepatoxicity or microsomal induction. Expression profiles from male Sprague-Dawley rats or in vitro systems treated for 24 h were measured by DNA oligonucleotide microarrays containing 8700 probe sets. Qualitative comparison of expression revealed a >80% concordance between in vivo liver and both in vitro systems; however, the responsiveness of both in vitro systems to compound-induced changes in gene expression was far less than that of in vivo. Furthermore, both in vitro systems appeared similar in their ability to reproduce compound-induced changes in gene expression observed in vivo.


Subject(s)
Gene Expression Profiling/methods , Hepatocytes/drug effects , Liver/drug effects , Xenobiotics/toxicity , Animals , Cells, Cultured , Hepatocytes/metabolism , In Vitro Techniques , Liver/cytology , Liver/metabolism , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Oligonucleotide Array Sequence Analysis/methods , Predictive Value of Tests , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Xenobiotics/metabolism
15.
Toxicol Sci ; 72(1): 31-42, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12604832

ABSTRACT

High MTBE exposures caused rat Leydig cell (LC) tumors in inhalation and gavage cancer bioassays. Investigating early endocrine changes consistent with known mechanisms of LC carcinogenesis, we gavaged adult male Sprague-Dawley rats with MTBE in five different subchronic experiments and studied testosterone biosynthesis in isolated rat LCs exposed in vitro to MTBE or a major metabolite, t-butanol. In vitro LC testosterone production declined 29-50% following 3-h exposures to 50-100 mM MTBE or t-butanol. Within hours after gavaging with 1,000 or 1,500 mg/kg MTBE, circulating testosterone declined to 38-49% of control (p < 0.05). If sampled longer after treatment or with lower doses, testosterone reductions were less dramatic or nondetectable even after 28 days of treatment. Accessory organ:brain weight ratios decreased only slightly although showing dose response with 40-800 mg/kg/day after 28 days. High MTBE doses caused slight liver weight and total P450 increases. Reduced aromatase activity in liver and testis microsomes predicted low serum estradiol, but estradiol was 19% higher than corn oil controls concurrent with testosterone reduction 1 h after the last of 14 daily 1,200-mg/kg doses (p < 0.05). Pituitary luteinizing hormone (LH) and prolactin measured in both intact and orchiectomized rats, with testosterone implants in some castrated rats providing stable levels of testosterone, revealed no consistent direct effect on hypothalamic-pituitary function. MTBE-treated rat livers showed no evidence of peroxisome proliferation, a characteristic of some LC carcinogens. Considering recognized mechanisms of Leydig cell cancer in rats, collectively these results suggested reduced LC steroidogenesis enzyme activity as a possible mechanism underlying MTBE LC carcinogenesis.


Subject(s)
Carcinogens/toxicity , Leydig Cell Tumor/metabolism , Methyl Ethers/toxicity , Administration, Inhalation , Animals , Aromatase/metabolism , Carcinogens/adverse effects , Corticosterone/metabolism , Cytochrome P-450 Enzyme System/metabolism , Estradiol/metabolism , Gonadotropins/metabolism , Leydig Cell Tumor/chemically induced , Leydig Cell Tumor/pathology , Luteinizing Hormone/metabolism , Male , Methyl Ethers/adverse effects , Orchiectomy , Organ Size/drug effects , Peroxisomes/physiology , Pituitary Hormones/metabolism , Rats , Rats, Sprague-Dawley , Solvents/toxicity , Testosterone/blood , Testosterone/metabolism , Toxicity Tests, Chronic , Tumor Cells, Cultured , Weight Gain/drug effects
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