Abstract:
BACKGROUND:Microcystin-LR, a cyclic heptapeptide, possesses the ability to inhibit the serine/threonine protein phosphatases PP1 and PP2A and, consequently, exhibits acute hepatocytotoxicity. Moreover, microcystin-LR induces cellular proliferation, resulting in tumor-promoting activity in hepatocytes. However, mechanisms that regulate the balance between cell death and proliferation after microcystin-LR treatment remain unclear. OBJECTIVE:We examined the contribution of the transcription factor p53, as well as that of the hepatic uptake transporter for microcystin-LR, organic anion transporting polypeptide 1B3 (OATP1B3), to the cellular response to microcystin-LR exposure. METHODS:We analyzed intracellular signaling responses to microcystin-LR by immunoblotting and real-time reverse-transcriptase polymerase chain reaction techniques using HEK293 human embryonic kidney cells stably transfected with SLCO1B3 (HEK293-OATP1B3). In addition, we analyzed the effect of attenuation of p53 function, via the p53 inhibitor pifithrin-alpha, and knockdown of p53 mRNA on the cytotoxicity of microcystin-LR using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS:Microcystin-LR induced the phosphorylation and accumulation of p53 in HEK293-OATP1B3 cells, which resulted in up-regulation of the expression of p53 transcript targets, including p21 and seven in absentia homolog 1 (siah-1). In addition, microcystin-LR activated Akt signaling through the phosphorylation of Akt and glycogen synthase kinase 3beta. Although Akt signaling was activated, the accumulation of p53 led cells to apoptosis after treatment with 50 nM microcystin-LR for 24 hr. Both pharmacological inhibition of transcription factor activity of p53 by pifithrin-alpha and knockdown of p53 with small hairpin RNA attenuated the susceptibility of HEK293-OATP1B3 cells to microcystin-LR. CONCLUSIONS:This study demonstrates the importance of p53 in the regulation of cell fate after exposure to microcystin-LR. Our results suggest that, under conditions of p53 inactivation (including p53 mutation), chronic exposure to low doses of microcystin-LR may lead to cell proliferation through activation of Akt signaling. Results of this study may contribute to the development of chemoprevention and chemotherapeutic approaches to microcystin-LR poisoning.
journal_name
Environ Health Perspectjournal_title
Environmental health perspectivesauthors
Takumi S,Komatsu M,Furukawa T,Ikeda R,Sumizawa T,Akenaga H,Maeda Y,Aoyama K,Arizono K,Ando S,Takeuchi Tdoi
10.1289/ehp.1001899subject
Has Abstractpub_date
2010-09-01 00:00:00pages
1292-8issue
9eissn
0091-6765issn
1552-9924journal_volume
118pub_type
杂志文章abstract::The toxicity of cadmium is determined by chelation reactions: in vivo, Cd2+ exists exclusively in coordination complexes with biological ligands, or with administered chelating agents. The Cd2+ ion has some soft character, but it is not a typical soft ion. It has a high degree of polarizability, and its complexes with...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8454249
更新日期:1984-03-01 00:00:00
abstract:BACKGROUND:Exposure to organophosphate (OP) pesticides is an occupational hazard for farmworkers and affects their children through the take-home pathway. OBJECTIVES:We examined the effectiveness of a randomized community intervention to reduce pesticide exposure among farmworkers and their children. METHODS:We condu...
journal_title:Environmental health perspectives
pub_type: 杂志文章,随机对照试验
doi:10.1289/ehp.10882
更新日期:2008-05-01 00:00:00
abstract::The Environmental Public Health Tracking Network (EPHTN) proposes to link environmental hazards and exposures to health outcomes. Statistical methods used in case-control and cohort studies to link health outcomes to individual exposure estimates are well developed. However, reliable exposure estimates for many contam...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.7145
更新日期:2004-10-01 00:00:00
abstract::One of the many forms that biological warfare may take is the targeting of major food crops. In a poor country where millions of citizens depend on staple crops such as rice, an act of bioterrorism that destroys the crop would create a famine, resulting not only in malnutrition and starvation but also in reduced immun...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.108-a126
更新日期:2000-03-01 00:00:00
abstract::Di(2-ethylhexyl) phthalate (DEHP) is used to make polyvinyl chloride (PVC) plastic tubing soft and flexible. Animal data show that adverse effects of DEHP exposure may include reduced fertility, reduced sperm production in males, and ovarian dysfunction in females. Known treatments that involve high DEHP exposures are...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.6901
更新日期:2004-09-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8352257
更新日期:1983-10-01 00:00:00
abstract::The knowledge of specific problems of occupational cancer in Spain is scarce. The environment of the workplace has improved over the last few years after a long period distinguished by bad working conditions, incomplete legislation, and insufficient safety measures and control. It has been estimated that 3,083,479 wor...
journal_title:Environmental health perspectives
pub_type: 杂志文章,评审
doi:10.1289/ehp.107-1566267
更新日期:1999-05-01 00:00:00
abstract::Two remote maritime populations were evaluated for their biological exposure to organochlorines in 1989-1990. Because of their high intake of seafood, these two populations have high biological levels. One hundred nine breast milk samples from Inuit women from Arctic Québec were analyzed to determine levels of polychl...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.94102s1205
更新日期:1994-01-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.0901303
更新日期:2010-04-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.85-1568331
更新日期:1990-04-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
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更新日期:2020-04-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.1307518
更新日期:2014-04-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8562177
更新日期:1985-10-01 00:00:00
abstract::The normal mucociliary epithelium of the respiratory tract in chronic cigarette smokers often is replaced focally by a metaplastic squamous epithelium. Because asbestos workers who smoke have a substantially greater risk of bronchogenic carcinoma than nonsmokers, we hypothesized that interaction of asbestos with squam...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.835127
更新日期:1983-09-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章,评审
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更新日期:1995-05-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.00108s2307
更新日期:2000-05-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.94102s7113
更新日期:1994-11-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章,meta分析,评审
doi:10.1289/ehp/1408092
更新日期:2014-09-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.11502
更新日期:2009-02-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章,评审
doi:10.1289/ehp.02110s6919
更新日期:2002-12-01 00:00:00
abstract:BACKGROUND:Studies suggest that phthalate exposures may adversely affect child respiratory health. OBJECTIVES:We evaluated associations between asthma diagnosed in children between 5 and 11 years of age and prenatal exposures to butylbenzyl phthalate (BBzP), di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEH...
journal_title:Environmental health perspectives
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doi:10.1289/ehp.1307670
更新日期:2014-10-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章,评审
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更新日期:2010-08-01 00:00:00
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journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.59-1568101
更新日期:1985-02-01 00:00:00
abstract::Haloalkane toxicity originates from attack on biological targets by reactive intermediates derived from haloalkane metabolism by a hemoprotein, cytochrome P-450. Carbon-centered radicals and their peroxyl derivatives are most likely involved. The reactions of iron porphyrin--a model for cytochrome P-450--with various ...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.856453
更新日期:1985-12-01 00:00:00
abstract::The identification of certain organic compounds in drinking water has led water treatment specialists to be increasingly concerned about the eventual risks of such pollutants to the health of consumers. Our experiments focused on the role of ozone and granular activated carbon in removing mutagenic compounds and precu...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8669159
更新日期:1986-11-01 00:00:00
abstract:BACKGROUND:Several per- and polyfluoroalkyl substances (PFAS) are ubiquitous anthropogenic pollutants almost universally detected in humans. Experimental evidence indicates that PFAS alter glucose metabolism and insulin secretion. However, epidemiological studies have yielded inconsistent results. OBJECTIVE:We sought ...
journal_title:Environmental health perspectives
pub_type: 杂志文章,随机对照试验
doi:10.1289/EHP1612
更新日期:2017-10-02 00:00:00
abstract::In numerous in vivo systems it has been shown that diets high in menhaden oil (a fish oil high in omega-3 fatty acids) can inhibit the carcinogenic process. In the present study, we have assessed the effects of a diet containing menhaden oil on 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-DNA adduct formation in targe...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.94102s657
更新日期:1994-10-01 00:00:00
abstract::We examined the estrogenicity of binary mixtures of the hydroxylated polychlorinated biphenyls (OHPCBs) 2,4,6-trichloro-4'-biphenylol (2,4,6-TCB-4'-OH) and 2,3,4,5-tetrachloro-4'-biphenylol and the pesticides endosulfan and dieldrin. The OHPCBs and pesticides were tested in both the MCF-7 focus assay and a competitive...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.98106s41041
更新日期:1998-08-01 00:00:00
abstract:BACKGROUND:One of the most widely used classes of insecticides is the synthetic pyrethroids. Although pyrethroids are less acutely toxic to humans than to insects, in vitro studies have suggested that pyrethroids may be estrogenic. OBJECTIVES:We assessed pubertal effects by orally administering 0.5, 1.0, and 5.0 mg/kg...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.11119
更新日期:2008-09-01 00:00:00
abstract::Although press reports indicate that the leakage of methyl isocyanate (MIC) on December 3, 1984, in Bhopal has led to an increase in spontaneous abortions, stillbirths, infant mortality, and fetal abnormalities, no clinical or experimental studies on the reproductive toxicity of MIC were reported in scientific journal...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8772153
更新日期:1987-06-01 00:00:00