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1.
Risk Anal ; 39(12): 2604-2607, 2019 12.
Article in English | MEDLINE | ID: mdl-31797415
2.
Risk Anal ; 39(10): 2272-2294, 2019 10.
Article in English | MEDLINE | ID: mdl-30980426

ABSTRACT

Over time, concerns have been raised regarding the potential for human exposure and risk from asbestos in cosmetic-talc-containing consumer products. In 1985, the U.S. Food and Drug Administration (FDA) conducted a risk assessment evaluating the potential inhalation asbestos exposure associated with the cosmetic talc consumer use scenario of powdering an infant during diapering, and found that risks were below levels associated with background asbestos exposures and risk. However, given the scope and age of the FDA's assessment, it was unknown whether the agency's conclusions remained relevant to current risk assessment practices, talc application scenarios, and exposure data. This analysis updates the previous FDA assessment by incorporating the current published exposure literature associated with consumer use of talcum powder and using the current U.S. Environmental Protection Agency's (EPA) nonoccupational asbestos risk assessment approach to estimate potential cumulative asbestos exposure and risk for four use scenarios: (1) infant exposure during diapering; (2) adult exposure from infant diapering; (3) adult exposure from face powdering; and (4) adult exposure from body powdering. The estimated range of cumulative asbestos exposure potential for all scenarios (assuming an asbestos content of 0.1%) ranged from 0.0000021 to 0.0096 f/cc-yr and resulted in risk estimates that were within or below EPA's acceptable target risk levels. Consistent with the original FDA findings, exposure and corresponding health risk in this range were orders of magnitude below upper-bound estimates of cumulative asbestos exposure and risk at ambient levels, which have not been associated with increased incidence of asbestos-related disease.


Subject(s)
Air Pollutants/toxicity , Asbestos/toxicity , Environmental Exposure , Powders , Risk Assessment , Talc/toxicity , Humans , Risk Factors
3.
Am J Bot ; 103(9): 1607-17, 2016 09.
Article in English | MEDLINE | ID: mdl-27638918

ABSTRACT

PREMISE OF THE STUDY: California experienced severe drought between 2012 and 2016. During this period, we compared seasonal changes in tissue-water relations among eight fern species in the Santa Monica Mountains of southern California to elucidate differential mechanisms of drought survival and physiological performance during extreme water deficits. METHODS: We monitored seasonal changes in water potential (Ψmd) and dark-adapted chlorophyll fluorescence (Fv/Fm), assessed tissue-water relations including osmotic potential at saturation and the turgor loss point (Ψπ, sat and Ψπ, tlp), and measured, for two evergreen species, xylem-specific and leaf-specific hydraulic conductivity (Ks and Kl) and vulnerability of stem xylem to water stress-induced embolism (water potential at 50% loss hydraulic conductivity, Ψ50). KEY RESULTS: Species grew in either riparian or chaparral understory. The five chaparral species had a wider range of seasonal water potentials, root depths, and frond phenological traits, including one evergreen, two summer-deciduous, and two desiccation-tolerant (resurrection) species. Evergreen species were especially diverse, with an evergreen riparian species maintaining seasonal water potentials above -1.3 MPa, while an evergreen chaparral species had seasonal water potentials below -8 MPa. In those two species the Ψ50 values were -2.5 MPa and -4.3 MPa, respectively. CONCLUSIONS: Observed differences in physiological performance among eight fern species reflected niche partitioning in water utilization and habitat preference associated with distinct phenological traits. We predict differential survival among fern species as future drought events in California intensify, with desiccation-tolerant resurrection ferns being the most resistant.


Subject(s)
Climate Change , Droughts , Ferns/metabolism , California , Desiccation , Ecosystem , Seasons , Species Specificity , Water/metabolism
6.
Scand J Work Environ Health ; 37(2): 147-58, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20941467

ABSTRACT

OBJECTIVES: Benzene is a natural constituent of crude oil and natural gas (0.1-3.0% by volume). Materials that are refined from crude oil and natural gas contain some residual benzene. Few datasets have appeared in the peer-reviewed literature characterizing exposures to benzene at specific refineries or during specific tasks. In this study, historical samples of airborne benzene collected from 1977-2005 at the ExxonMobil Baton Rouge, Louisiana, USA, docks were evaluated. METHODS: Workers were categorized into 11 job titles, and both non-task (≤180 min sample duration) and task-related (<180 min) benzene concentrations were assessed. Approximately 800 personal air samples (406 non-task and 397 task-related) were analyzed. RESULTS: Non-task samples showed that concentrations varied significantly across job titles and generally resulted from exposures during short-duration tasks such as tank sampling. The contractor - tankerman job title had the highest average concentration [N=38, mean 1.4 parts per million (ppm), standard deviation (SD) 2.6]. Task-related samples indicated that the highest exposures were associated with the disconnection of cargo loading hoses (N=134, mean 11 ppm, SD 32). Non-task samples for specific job categories showed that concentrations have decreased over the past 30 years. Recognizing the potential for benzene exposure, this facility has required workers to use respiratory protective equipment during selected tasks and activities; thus, the concentrations measured were likely greater than those that the employee actually experienced. CONCLUSIONS: This study provides a job title- and task-focused analysis of occupational exposure to benzene during dock facility operations that is insightful for understanding the Baton Rouge facility and others similar to it over the past 30 years.


Subject(s)
Air Pollutants, Occupational/analysis , Benzene/analysis , Chemical Industry , Occupational Exposure , Petroleum , Air Pollutants, Occupational/adverse effects , Benzene/adverse effects , Humans , Limit of Detection , Louisiana , Respiratory Protective Devices
7.
J Expo Sci Environ Epidemiol ; 21(2): 169-85, 2011.
Article in English | MEDLINE | ID: mdl-19865071

ABSTRACT

Although occupational benzene exposure of refinery workers has been studied for decades, no extensive analysis of historical industrial hygiene data has been performed focusing on airborne concentrations at specific refineries and tasks. This study characterizes benzene exposures at the ExxonMobil Baytown, TX, refinery from 1978 to 2006 to understand the variability in workers' exposures over time and during different job tasks. Exposures were grouped by operational status, job title, and tasks. More than 9000 industrial hygiene air samples were evaluated; approximately 4000 non-task (> 3 h) and 1000 task-related (< 3 h) personal samples were considered. Each sample was assigned to one of 27 job titles, 29 work areas, and 16 task bins (when applicable). Process technicians were sampled most frequently, resulting in the following mean benzene concentrations by area: hydrofiner (n=245, mean=1.3 p.p.m.), oil movements (n=286, mean=0.23 p.p.m.), reformer (n=575, mean=0.10 p.p.m.), tank farm (n=9, mean=0.65 p.p.m.), waste treatment (n=446, mean=0.13 p.p.m.), and other areas (n=460, mean=0.062 p.p.m.). The most frequently sampled task was sample collection (n=218, mean=0.40 p.p.m.). Job title and area did not significantly impact task-related exposures. Airborne concentrations were significantly lower after 1990 than before 1990. Results of this task-focused study may be useful when analyzing benzene exposures at other refineries.


Subject(s)
Air Pollutants, Occupational/analysis , Benzene/analysis , Extraction and Processing Industry , Occupational Exposure/analysis , Petroleum , Air Pollutants, Occupational/chemistry , History, 20th Century , History, 21st Century , Humans , Inhalation Exposure/analysis , Occupational Exposure/history , Risk Assessment/methods , Texas , Time Factors , Workplace
8.
Toxicol Ind Health ; 26(10): 671-90, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20643709

ABSTRACT

While petroleum industry studies have indicated low benzene exposure potential for refinery workers, most provide limited data for assessing job or task-related benzene exposures. This study characterizes job and task-specific airborne benzene concentrations and variability over time for the ExxonMobil refinery in Joliet, Illinois from 1977 to 2006. A database of 2289 industrial hygiene air samples, including 1145 non-task (≥180 min) personal samples and 480 task-related (<180 min) personal samples, were analyzed. Samples were grouped by operational status, job, and task. Benzene concentrations were determined for each job category and task bin, with additional analyses conducted to determine whether benzene concentrations changed over time. The results indicate that the benzene concentrations for non-task and task samples were relatively low. For all non-task samples, the arithmetic mean benzene concentration was 0.12 part per million (ppm). The most frequently sampled workers (process technicians during routine operations) had an arithmetic mean benzene concentration of 0.038 ppm. The most frequently sampled task bin (blinding and breaking) had an arithmetic mean benzene concentration of 1.0 ppm. This study provides benzene air concentration data that can be used in combination with job histories to reconstruct historical benzene exposures for workers at the Joliet Refinery over the past 30 years.


Subject(s)
Air Pollutants, Occupational/analysis , Air Pollution/statistics & numerical data , Benzene/analysis , Occupational Exposure/analysis , Extraction and Processing Industry , Humans , Illinois , Occupational Exposure/statistics & numerical data
9.
Int J Hyg Environ Health ; 213(4): 285-301, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20494616

ABSTRACT

Because crude oil and refined petroleum products can contain benzene and benzene is considered a known carcinogen by numerous independent and governmental agencies, including the International Agency for Cancer Research, the petroleum industry has implemented exposure control programs for decades. As part of the benzene control programs, significant exposure assessments have been performed; both qualitatively and through quantitative measurements. In this study, we evaluated the airborne concentrations of benzene and their variability over time at the ExxonMobil refinery in Beaumont, TX between 1976 and 2007. The results of 5854 personal air samples are included in this analysis; 3761 were considered non-task (> or =180 min) personal samples, and 2093 were considered task-related (<180 min) personal samples. Dock and loading rack samples were analyzed separately from the refinery samples because in addition to refinery products, employees at the dock and loading rack also handled chemical plant products. In general, the non-task personal refinery air samples indicated that exposures of the past 30 years were generally below the occupational exposure limit of 1 ppm (mean=0.30 ppm, SD=3.1), were higher during routine (mean=0.32 ppm, SD=3.3) than turnaround operations (mean=0.16 ppm, SD=0.87), and decreased slightly over time. The job sampled most frequently during routine operations was that of process technician, and, as broken down by area, resulted in the following mean benzene air concentrations: coker (n=146, mean=0.014 ppm, SD=0.036), lube extraction unit (n=31, mean<0.070 ppm), pipestills (n=136, mean=0.12, SD=0.47), waste treatment (n=107, mean=0.20, SD=0.28), and all other areas (n=1115, mean=0.059 ppm, SD=0.36). Task-based samples indicated that the highest exposures resulted from the tank cleaning tasks, although the overall task mean benzene air concentration was 1.4 ppm during routine operations. The most frequently sampled task during routine operations was blinding and breaking, and the mean benzene air concentrations associated with this task were statistically higher in the reformer area of the refinery (n=311, mean=3.2 ppm, SD=7.9) than in all other areas (n=200, mean=0.92 ppm, SD=3.1). However, task-related exposures were found to be statistically similar across job categories for a given task. This study thus provides a task-focused analysis for occupational exposure to benzene during refinery operations, and will be useful for understanding exposures at this refinery.


Subject(s)
Air Pollutants/analysis , Benzene/analysis , Occupational Exposure/analysis , Petroleum , Environmental Monitoring , Extraction and Processing Industry , Humans , Texas
10.
Neurosurgery ; 66(3 Suppl Operative): 1-3; discussion 3, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20124929

ABSTRACT

BACKGROUND: Knowledge of the anatomy of ligaments that bind the craniocervical junction is important for treating patients with lesions of this region. Although the anatomy and function of these ligaments have been well described, those of the transverse occipital ligament (TOL) have remained enigmatic. OBJECTIVE: To describe the anatomy and functions of the transverse occipital ligament. METHODS: Via a posterior approach, 9 cadaveric specimens underwent dissection of the craniocervical junction with special attention to the presence and anatomy of the TOL. RESULTS: The TOL was identified in 77.8% of the specimens. The ligament was found to be rectangular with fibers running horizontally between the lateral aspects of the foramen magnum. The attachment of each ligament near the occipital condyle was consistent, and each ligament was found superior to the transverse portion of the cruciform ligament and inserted just posterior to the lateral attachment sites of the alar ligaments. The average width, length, and thickness of the TOL was 0.34, 1.94, and 0.13 cm, respectively. The TOL in some specimens also had connections to the alar and transverse ligaments. CONCLUSION: The TOL was found in the majority of our specimens. The possible functions of this ligament when attached to the alar ligaments include providing additional support to these structures in stabilizing lateral bending, flexion, and axial rotation of the head. Knowledge of this ligament may aid in further understanding craniocervical stability and help in differentiating normal from pathology via imaging modalities.


Subject(s)
Atlanto-Axial Joint/anatomy & histology , Atlanto-Occipital Joint/anatomy & histology , Foramen Magnum/anatomy & histology , Ligaments/anatomy & histology , Occipital Bone/anatomy & histology , Aged , Atlanto-Axial Joint/physiology , Atlanto-Occipital Joint/physiology , Axis, Cervical Vertebra/anatomy & histology , Axis, Cervical Vertebra/physiology , Cadaver , Cervical Atlas/anatomy & histology , Cervical Atlas/physiology , Dissection/methods , Female , Foramen Magnum/physiology , Head Movements/physiology , Humans , Ligaments/physiology , Male , Middle Aged , Occipital Bone/physiology , Odontoid Process/anatomy & histology , Odontoid Process/physiology , Range of Motion, Articular/physiology
11.
Rom J Morphol Embryol ; 50(4): 689-91, 2009.
Article in English | MEDLINE | ID: mdl-19942967

ABSTRACT

BACKGROUND: There is a paucity in the literature regarding the reflected ligament. Therefore, the present study was performed in order to further elucidate this anatomy. MATERIAL AND METHODS: Eighteen formalin-fixed adult cadavers (35 sides) underwent dissection of the medial inguinal region. The reflected ligament was observed for and when identified, its dimensions were measured. RESULTS: 83% of sides were found to have a reflected ligament. These were identified in 16 male and 13 female bodies. The size and shape for the reflected ligaments were variable but overall, triangular in nature. In general, the reflected ligament was found to extend from the lacunar and medial inguinal ligaments and extended obliquely toward the midline at an approximate 45 degrees angle to insert near the linea alba. Two ligaments (6.9 %) were identified that interdigitated with the contralateral reflected ligament. The medial and lateral lengths of the ligament had a mean measurement of 2.28 and 2.58 cm. The base of the reflected ligament had a mean of 2.52 cm and the height of this ligament was found to have a mean of 2.56 cm. The mean area of the reflected ligament was calculated as 2.93 cm(2). There was no statistically significant difference between right or left sides or between genders. CONCLUSIONS: The reflected ligament was identified in the majority of our specimens and this structure usually contributed to the formation of the posteromedial wall of the external inguinal ring. Therefore, this fact should be included in future descriptions of this ligament.


Subject(s)
Inguinal Canal/anatomy & histology , Ligaments/anatomy & histology , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged
12.
J Occup Environ Hyg ; 6(9): 517-29, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19544135

ABSTRACT

Because crude oil contains up to 3% benzene and there is an association between high chronic exposure to appreciable concentrations of benzene and acute myelogenous leukemia, exposure of refinery workers has been studied for many years. To date, no extensive industrial hygiene exposure analyses for historical benzene exposure have been performed, and none have focused on the airborne concentrations in the workplace at specific refineries or for specific tasks. In this study, the authors evaluated the airborne concentrations of benzene and their variability over time at the ExxonMobil refinery in Baton Rouge between 1977 and 2005. Refinery workers were categorized into 117 worker groups using company job descriptions. These 117 groups were further collapsed into 25 job categories based on similarity of measured exposure results. Results of 5289 personal air samples are included in this analysis; 3403 were considered nontask (>or= 180 min) personal samples, and 830 were considered task-related (< 180 min) personal samples; the remainder did not fit in either category. In general, nontask personal air samples indicated that exposures of the past 30 years were generally below the occupational exposure limit of 1 ppm, but there was only a small, decreasing temporal trend in the concentrations. The job sampled most frequently during routine operations was process technician and, as broken down by area, resulted in the following mean benzene concentrations: analyzers (mean = 0.12 ppm), coker (mean = 0.013 ppm), hydrofiner (mean = 0.0054 ppm), lube blending and storage (mean = 0.010 ppm), waste treatment (mean = 0.092 ppm), and all other areas (mean = 0.055 ppm). Task-based samples indicated that the highest exposures resulted from the sampling tasks, specifically from those performed on process materials; in general, though, even these tasks had concentrations well below the STEL of 5 ppm. The most frequently sampled task was gauging (mean = 0.12 ppm). Task-related exposures were also similar across job categories for a given task, with a few exceptions. This study thus provides a task-focused analysis for occupational exposure to benzene during refinery operations, which can be insightful for understanding exposures at this refinery and perhaps others operated since about 1975.


Subject(s)
Air Pollutants, Occupational/analysis , Benzene/analysis , Extraction and Processing Industry , Occupational Exposure/analysis , Petroleum , Extraction and Processing Industry/history , History, 20th Century , Humans , Inhalation Exposure/analysis , Inhalation Exposure/classification , Louisiana , Occupational Exposure/classification , Time , Workplace/classification
13.
Toxicol Appl Pharmacol ; 225(3): 267-77, 2007 Dec 15.
Article in English | MEDLINE | ID: mdl-17950772

ABSTRACT

Administration of peroxisome proliferators to rodents causes proliferation of peroxisomes, induction of beta-oxidation enzymes, hepatocellular hypertrophy and hyperplasia, with chronic exposure ultimately leading to hepatocellular carcinomas. Many responses associated with peroxisome proliferators are nuclear receptor-mediated events involving peroxisome proliferators-activated receptor alpha (PPARalpha). A role for nuclear receptor-independent events has also been shown, with evidence of Kupffer cell-mediated free radical production, presumably through NAPDH oxidase, induction of redox-sensitive transcription factors involved in cytokine production and cytokine-mediated cell replication following acute treatment with peroxisome proliferators in rodents. Recent studies have demonstrated, by using p47(phox)-null mice which are deficient in NADPH oxidase, that this enzyme is not related to the phenotypic events caused by prolonged administration of peroxisome proliferators. In an effort to determine the timing of the transition from Kupffer cell-to PPARalpha-dependent modulation of peroxisome proliferator effects, gene expression was assessed in liver from Pparalpha-null, p47(phox)-null and corresponding wild-type mice following treatment with 4-chloro-6-(2,3-xylidino)-pyrimidynylthioacetic acid (WY-14,643) for 8 h, 24 h, 72 h, 1 week or 4 weeks. WY-14,643-induced gene expression in p47(phox)-null mouse liver differed substantially from wild-type mice at acute doses and striking differences in baseline expression of immune related genes were evident. Pathway mapping of genes that respond to WY-14,643 in a time- and dose-dependent manner demonstrates suppression of immune response, cell death and signal transduction and promotion of lipid metabolism, cell cycle and DNA repair. Furthermore, these pathways were largely dependent on PPARalpha, not NADPH oxidase demonstrating a temporal shift in response to peroxisome proliferators. Overall, this study shows that NADPH oxidase-dependent events, while detectable following acute treatment, are transient. To the contrary, a strong PPARalpha-specific gene signature was evident in mice that were continually exposed to WY-14,643.


Subject(s)
Gene Expression Regulation/drug effects , Kupffer Cells/drug effects , Liver/drug effects , Oligonucleotide Array Sequence Analysis/methods , PPAR alpha/drug effects , Peroxisome Proliferators/toxicity , Pyrimidines/toxicity , Animals , Gene Expression Profiling , Kupffer Cells/metabolism , Liver/metabolism , Male , Mice , Mice, Knockout , NADPH Oxidases/metabolism , PPAR alpha/metabolism , Time Factors
14.
Toxicol Sci ; 98(2): 366-74, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17483499

ABSTRACT

Long-term exposure of rodents to peroxisome proliferators leads to increases in peroxisomes, hepatocellular proliferation, oxidative damage, suppressed apoptosis, and ultimately results in the development of hepatic adenomas and carcinomas. Peroxisome proliferators-activated receptor (PPAR)alpha was shown to be required for these pleiotropic responses; however, Kupffer cells, resident liver macrophages, were also identified as playing a role in peroxisome proliferators-induced effects, independently of PPARalpha. Previous studies showed that oxidants from NADPH (nicotinamide adenine dinucleotide phosphate, reduced) oxidase mediate acute effects of peroxisome proliferators in rodent liver. To determine if Kupffer cell oxidants are also involved in chronic effects, NADPH oxidase-deficient (p47(phox)-null) mice were fed 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (WY-14,643)-containing diet (0.1% wt/wt) for 1 week, 5 weeks, or 5 months along with Pparalpha-null and wild type mice. As expected, no change in liver size, cell replication rates, or other phenotypic effects of peroxisome proliferators were observed in Pparalpha-null mice. Through 5 months of treatment, the p47(phox)-null and wild type mice exhibited peroxisome proliferators-induced adverse liver effects, along with increased oxidative DNA damage and increased cell proliferation, a response that is potentially mediated through nuclear factor kappa B (NFkB). Suppressed apoptosis caused by WY-14,643 was dependent on both NADPH oxidase and PPARalpha. Collectively, these findings suggest that involvement of Kupffer cells in WY-14,643-induced parenchymal cell proliferation and oxidative stress in rodent liver is an acute phenomenon that is not relevant to long-term exposure, but they are still involved in chronic apoptotic responses. These results provide new insight for understanding the mode of hepatocarcinogenic action of peroxisome proliferators.


Subject(s)
Liver/drug effects , PPAR alpha/deficiency , Peroxisome Proliferators/toxicity , Pyrimidines/toxicity , Acyl-CoA Oxidase/metabolism , Animals , Apoptosis/drug effects , Body Weight/drug effects , Caspase 8/metabolism , Caspase 9/metabolism , Cell Cycle Proteins/metabolism , Cell Proliferation/drug effects , DNA Damage , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Knockout , NADPH Oxidases/deficiency , NADPH Oxidases/genetics , Organ Size/drug effects , Oxidative Stress , PPAR alpha/genetics
15.
Free Radic Biol Med ; 42(3): 335-42, 2007 Feb 01.
Article in English | MEDLINE | ID: mdl-17210446

ABSTRACT

Reactive oxygen species are thought to be crucial for peroxisome proliferator-induced liver carcinogenesis. Free radicals have been shown to mediate the production of mitogenic cytokines by Kupffer cells and cause DNA damage in rodent liver. Previous in vivo experiments demonstrated that acute administration of the peroxisome proliferator di(2-ethylhexyl) phthalate (DEHP) led to an increase in production of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts in liver, an event that was dependent on Kupffer cell NADPH oxidase, but not peroxisome proliferator-activated receptor (PPAR)alpha. Here, we hypothesized that continuous treatment with peroxisome proliferators will cause a sustained formation in POBN radical adducts in liver. Mice were fed diets containing either 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14,643, 0.05% w/w) or DEHP (0.6% w/w) for up to 3 weeks. Liver-derived radical production was assessed in bile samples by measuring POBN radical adducts using electron spin resonance. Our data indicate that WY-14,643 causes a sustained increase in POBN radical adducts in mouse liver and that this effect is greater than that of DEHP. To understand the molecular source of these radical species, NADPH oxidase-deficient (p47phox-null) and PPARalpha-null mice were examined after treatment with WY-14,643. No increase in radicals was observed in PPARalpha-null mice that were treated with WY-14,643 for 3 weeks, while the response in p47phox-nulls was similar to that of wild-type mice. These results show that PPARalpha, not NADPH oxidase, is critical for a sustained increase in POBN radical production caused by peroxisome proliferators in rodent liver. Therefore, peroxisome proliferator-induced POBN radical production in Kupffer cells may be limited to an acute response to these compounds in mouse liver.


Subject(s)
Liver/drug effects , NADPH Oxidases/metabolism , PPAR alpha/metabolism , Peroxisome Proliferators/pharmacology , Pyridines/metabolism , Animals , Diethylhexyl Phthalate/pharmacology , Free Radicals/metabolism , Kupffer Cells/metabolism , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NADPH Oxidases/genetics , PPAR alpha/genetics , Peroxisome Proliferators/metabolism , Pyrimidines/pharmacology , Reactive Oxygen Species/metabolism
16.
J Biol Chem ; 280(10): 9519-27, 2005 Mar 11.
Article in English | MEDLINE | ID: mdl-15632134

ABSTRACT

Recent work has shown that peroxisome proliferator-activated receptor beta (PPARbeta) attenuates cell proliferation and skin carcinogenesis, and this is due in part to regulation of ubiquitin C expression. In these studies, the role of PPARbeta in modulating ubiquitin-dependent protein kinase Calpha (PKCalpha) levels and phosphorylation signaling pathways was evaluated. Intracellular phosphorylation analysis showed that phosphorylated PKCalpha and other kinases were lower in wild-type mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) as compared with PPARbeta-null mouse skin. No differences in expression levels of other PKC isoforms present in skin were observed. Lower ubiquitination of PKCalpha was found in TPA-treated PPARbeta-null skin as compared with wild-type, and inhibition of ubiquitin-dependent proteasome degradation prevented TPA-induced down-regulation of PKCalpha. The activity of PKCalpha and downstream signaling kinases is enhanced, and expression of cyclooxygenase-2 (COX-2) is significantly greater, in PPARbeta-null mouse skin in response to TPA compared with wild-type mouse skin. Inhibition of PKCalpha or COX-2 reduced cell proliferation in TPA-treated PPARbeta-null keratinocytes in a dose-dependent manner, whereas it only slightly influenced cell proliferation in wild-type keratinocytes. Combined, these studies provide strong evidence that PPARbeta attenuates cell proliferation by modulating PKCalpha/Raf1/MEK/ERK activity that may be due in part to reduced ubiquitin-dependent turnover of PKCalpha.


Subject(s)
Cell Division/physiology , PPAR gamma/physiology , PPAR-beta/physiology , Protein Kinase C/metabolism , Animals , Cells, Cultured , Epidermal Cells , In Vitro Techniques , Keratinocytes/drug effects , Keratinocytes/physiology , Mice , Mice, Knockout , PPAR-beta/deficiency , PPAR-beta/genetics , Phosphoproteins/metabolism , Phosphorylation , Protein Kinase C-alpha , Signal Transduction/drug effects , Skin/cytology , Skin/drug effects , Skin/metabolism , Tetradecanoylphorbol Acetate/pharmacology , Ubiquitin/metabolism
17.
Carcinogenesis ; 26(1): 219-27, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15447978

ABSTRACT

Prolonged administration of peroxisome proliferators to rodents typically leads to hepatocarcinogenesis. Peroxisome proliferator-activated receptor-alpha (PPARalpha) is required to mediate alterations in PPARalpha target gene expression, repress apoptosis, enhance replicative DNA synthesis, oxidative stress to DNA and hepatocarcinogenesis induced by the relatively specific PPARalpha agonist, Wy-14,643. Interestingly, administration of the less specific PPARalpha agonist, bezafibrate, leads to a modest induction of PPARalpha target genes in the absence of PPARalpha expression. In these studies, the role of PPARalpha in modulating hepatocarcinogenesis induced by long-term feeding of 0.5% bezafibrate was examined in wild-type (+/+) and PPARalpha-null (-/-) mice. The average liver weight was significantly higher in (+/+) and (-/-) mice fed bezafibrate than controls, but this effect was considerably less in (-/-) mice as compared with similarly treated (+/+) mice. Increased levels of mRNA encoding cell cycle regulatory proteins and DNA repair enzymes were found in (+/+) mice fed bezafibrate, and this effect was not found in (-/-) mice. In mice fed bezafibrate for 1 year, preneoplastic foci, adenomas and a hepatocellular carcinoma were found in (+/+) mice, while only a single microscopic adenoma was found in one (-/-) mouse. This effect was observed in both Sv/129 and C57BL/6N strains of mice, although only preneoplastic foci were observed in the latter strain. Interestingly, hepatic cholestasis was observed in 100% of the bezafibrate-fed (-/-) mice, and this was accompanied by significantly elevated hepatic expression of mRNA encoding bile salt export pump and lower expression of mRNA encoding cytochrome P450 7A1, consistent with enhanced activation of the bile acid receptor, farnesoid X receptor. Results from these studies demonstrate that the PPARalpha is required to mediate hepatocarcinogenesis induced by bezafibrate, and that PPARalpha protects against potential cholestasis.


Subject(s)
Bezafibrate/metabolism , Cholestasis/chemically induced , Liver Neoplasms/metabolism , PPAR alpha/deficiency , Peroxisome Proliferators/toxicity , Acyl-CoA Oxidase/drug effects , Acyl-CoA Oxidase/metabolism , Animals , Bezafibrate/toxicity , Bile Acids and Salts/metabolism , Blotting, Northern , Cell Cycle Proteins/drug effects , Cell Cycle Proteins/metabolism , Cholestasis/metabolism , Cholestasis/pathology , Cytochrome P-450 CYP4A/drug effects , Cytochrome P-450 CYP4A/metabolism , DNA Repair Enzymes/drug effects , DNA Repair Enzymes/metabolism , DNA-Binding Proteins/drug effects , DNA-Binding Proteins/metabolism , Disease Models, Animal , Liver Neoplasms/chemically induced , Liver Neoplasms/pathology , Male , Mice , PPAR alpha/genetics , RNA, Messenger/analysis , Receptors, Cytoplasmic and Nuclear , Transcription Factors/drug effects , Transcription Factors/metabolism
18.
J Biol Chem ; 279(22): 23719-27, 2004 May 28.
Article in English | MEDLINE | ID: mdl-15033975

ABSTRACT

The role of peroxisome proliferator-activated receptor-beta (PPARbeta) in the molecular regulation of skin carcinogenesis was examined. Increased caspase-3 activity associated with apoptosis was found in the skin of wild-type mice after tumor promotion with 12-O-tetradecanoylphorbol-13-acetate, and this effect was diminished in PPARbeta-null mice. The onset of tumor formation, tumor size, and tumor multiplicity induced from a two-stage carcinogen bioassay (7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate) were significantly enhanced in PPARbeta-null mice compared with wild-type mice. To begin to characterize the molecular changes underlying this PPARbeta-dependent phenotype, microarray analysis was performed and a number of differentially regulated gene products were identified including ubiquitin C. Subsequent promoter analysis, reporter gene assays, site-directed mutagenesis, and electrophoretic mobility shift assays provide evidence that PPARbeta regulates ubiquitin C expression, and that ubiquitination of proteins is influenced by PPARbeta. These results strongly suggest that activation of PPARbeta-dependent target genes provides a novel strategy to inhibit tumor promotion and carcinogenesis.


Subject(s)
Receptors, Cytoplasmic and Nuclear/metabolism , Skin Neoplasms/metabolism , Transcription Factors/metabolism , Ubiquitin C/biosynthesis , Animals , Base Sequence , Cell Division/genetics , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cloning, Molecular , Gene Expression Regulation, Neoplastic , Mice , Molecular Sequence Data , Mutagenesis, Site-Directed , Promoter Regions, Genetic/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Skin Neoplasms/etiology , Skin Neoplasms/genetics , Transcription Factors/genetics , Ubiquitin C/genetics
19.
Biochim Biophys Acta ; 1632(1-3): 80-9, 2003 Jun 10.
Article in English | MEDLINE | ID: mdl-12782154

ABSTRACT

Bezafibrate is a known activator of peroxisome proliferator-activated receptors (PPARs) that can activate both PPARalpha and PPARbeta. To determine the role(s) of these receptors in mediating the biological effects of this chemical, the effect of bezafibrate was examined in PPARalpha-null and PPARbeta-null mice. Wild-type, PPARalpha-null, or PPARbeta-null mice were fed either a control diet or one containing 0.5% bezafibrate for 10 days. Bezafibrate feeding caused a significant increase in liver weight in wild-type and PPARbeta-null mice compared to controls, while liver weight was unchanged in bezafibrate-fed PPARalpha-null mice. Gonadal adipose stores were significantly smaller in wild-type and PPARbeta-null mice fed bezafibrate than in controls, and this effect was not found in similarly fed PPARalpha-null mice. Analysis of liver, white adipose tissue, and intestinal mRNAs showed that bezafibrate caused similar changes of mRNAs encoding lipid metabolizing enzymes in wild-type and PPARbeta-null mice compared to controls. Interestingly, in PPARalpha-null mice, bezafibrate also induced several mRNAs previously thought to be solely controlled by PPARalpha, showing that the effects of this drug are not exclusively modulated by this PPAR isoform. Western blot analysis of liver protein was consistent with changes in mRNA expression showing that the alterations in mRNA expression correlate with protein expression in this tissue. Results from these studies demonstrate that the effect of bezafibrate is mediated in large part by PPARalpha, although some changes in gene expression are dependent on PPARbeta. In contrast to other PPARalpha ligands such as WY-14,643, induction of some target genes by bezafibrate can also be modulated in the absence of a functional PPARalpha.


Subject(s)
Bezafibrate/pharmacology , Hypolipidemic Agents/pharmacology , Ligands , Receptors, Cytoplasmic and Nuclear/metabolism , Transcription Factors/metabolism , Adipose Tissue/drug effects , Animals , Female , Gene Expression Regulation/drug effects , Mice , Mice, Knockout , Organ Size/drug effects , Protein Isoforms/metabolism , RNA, Messenger/analysis , Triglycerides/blood
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