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2.
J Eur Acad Dermatol Venereol ; 32(8): 1368-1372, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29575357

RESUMO

BACKGROUND: Patients treated with vemurafenib for metastatic melanoma often develop skin lesions similar to those observed after exposure to dioxin-like compounds. We previously called these lesions MADISH (metabolizing acquired dioxin-induced skin hamartoma) when analysing a case of acute dioxin poisoning. OBJECTIVE: We performed a clinical trial aimed at comparing the skin lesions observed under vemurafenib treatment with MADISH in order to bring to light a possible crosstalk between vemurafenib and dioxin pathways. METHODS: In this case series study, we explored the histological aspect of skin lesions in 10 cases treated with vemurafenib for malignant melanoma. We also analysed the ability of vemurafenib and tyrosine kinase inhibitors to induce dioxin-AhR pathway. RESULTS: All patients had skin lesions diagnosed as 'non-inflammatory acneiform eruption' by dermatologists. These were predominantly facial with notable retroauricular involvement and clinically compatible with chloracne/MADISH when assessed by dioxin expert. Histological analysis showed mostly comedone-like lesions and dermal cysts containing epithelial wall with basal or lateral epithelial projections and lamellar keratinization and alterations of remaining sebaceous glands. The expression of CYP1A1, a gene highly induced following dioxin exposure, was not observed in these lesions. Vemurafenib and the tyrosine kinase inhibitors erlotinib and gefitinib did not induce CYP1A1 activity. DISCUSSION: Although the skin lesions under vemurafenib treatment were morphologically similar to MADISH, the absence of CYP1A1 expression in dermal cysts of patients and the absence of CYP1A1 activation by vemurafenib led us consider that these skin lesions were different from true MADISH and not mediated by a crosstalk of AhR signalling, but rather to a hyperactivation of PI3K-Akt pathway as a consequence of vemurafenib treatment. A strong expression of CYP1A1 in the epithelial wall of dermal cysts must be required, parallel to the morphology of the lesions, to make the diagnosis of MADISH, the hallmark of an exposure to dioxin-like/chloracnegen compounds.


Assuntos
Antineoplásicos/efeitos adversos , Cloracne/patologia , Cisto Epidérmico/metabolismo , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Vemurafenib/efeitos adversos , Antineoplásicos/farmacologia , Cloracne/etiologia , Cloracne/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Dioxinas/efeitos adversos , Erupção por Droga/etiologia , Erupção por Droga/metabolismo , Erupção por Droga/patologia , Ativação Enzimática/efeitos dos fármacos , Cisto Epidérmico/induzido quimicamente , Cloridrato de Erlotinib/farmacologia , Feminino , Gefitinibe/farmacologia , Células Hep G2 , Humanos , Masculino , Inibidores de Proteínas Quinases/farmacologia , Vemurafenib/farmacologia
3.
Skinmed ; 15(6): 485-488, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29282195

RESUMO

An 11-year-old boy presented with a 1-year history of multiple comedonal lesions distributed over his body. The lesions (Figure 1) were densely distributed throughout his body. Ophthalmologic examination revealed hyperpigmented conjunctival mucosae and enlarged meibomian glands (Figure 2). His nails were also hyperpigmented. In addition, he had been coughing and had a fever, each present for a month. Significant laboratory studies included mild anemia (hemoglobin 11.6 gm%) and leukocytosis of 20,800. A chest x-ray was suggestive of interstitial lung disease. Similar lesions were present on his two siblings and parents. Additionally, his father had developed multiple, acne-like lesions, large abscesses, palmar and plantar peeling, and severe jaundice with hepatic failure. He had a history of frequent exposure to a pesticide mixed with a herbicide, as a result of leakage from a spray container. The patient was diagnosed with chloracne, based on the history, clinical features, and histologic examination.


Assuntos
Agricultura , Cloracne/etiologia , Dermatite Ocupacional/etiologia , Exposição Ocupacional/efeitos adversos , Praguicidas/efeitos adversos , Criança , Cloracne/patologia , Dermatite Ocupacional/patologia , Família , Humanos , Masculino
5.
Chemosphere ; 185: 489-498, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28715759

RESUMO

Laboratory safety requires protecting personnel from chemical exposures. Working with stock solutions of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDFs) in routine analysis of feed and food with bioanalytical or physicochemical methods raises some concerns. Since PCDD/PCDFs are considered as possibly acutely toxic, the potential risks were evaluated to determine whether supervision of their use is necessary. Based on LD50-data for oral or dermal intake, hazard classification of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a substance (category 1) and in commercially available TCDD standard solutions (category 4) is different. As worst case exposure scenario during routine laboratory work it was assumed that a dose of 100 ng TCDD gets onto the skin and is absorbed. This would result in the total body burden of a 70 kg person with 15 kg fat increasing from 10 (upper range of current background levels) to ∼17 pg of toxic equivalents (TEQs) of PCDD/PCDFs per g lipid, a level commonly observed over past decades. Chloracne, the main acute effect occurring weeks after exposure, is observed at much higher blood concentrations than estimated from accidental laboratory exposure. Immunotoxicity, developmental effects and other toxic effects may occur at lower blood levels, but require longer periods to develop. Since acute toxic symptoms don't occur within an "8 h acute time window", no supervision is necessary when working with standard solutions in routine analysis. Nevertheless, precautionary measures are needed regarding long-term adverse health effects and appropriate workplace conditions must exist to ensure that additional occupational exposure to PCDD/PCDFs by laboratory personnel is negligible.


Assuntos
Benzofuranos/toxicidade , Exposição Ocupacional/análise , Dibenzodioxinas Policloradas/toxicidade , Carga Corporal (Radioterapia) , Cloracne/sangue , Cloracne/etiologia , Humanos , Laboratórios , Exposição Ocupacional/prevenção & controle , Exposição Ocupacional/normas , Risco , Fatores de Tempo
6.
J Prev Med Public Health ; 49(2): 80-96, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27055545

RESUMO

Recently, a series of lawsuits were filed in Korea claiming tort liability against tobacco companies. The Supreme Court has already issued decisions in some cases, while others are still pending. The primary issue in these cases is whether the epidemiological evidence submitted by the plaintiffs clearly proves the causal relationship between smoking and disease as required by civil law. Proving causation is difficult in tobacco lawsuits because factors other than smoking are involved in the development of a disease, and also because of the lapse of time between smoking and the manifestation of the disease. The Supreme Court (Supreme Court Decision, 2011Da22092, April 10, 2014) has imposed some limitations on using epidemiological evidence to prove causation in tobacco lawsuits filed by smokers and their family members, but these limitations should be reconsidered. First, the Court stated that a disease can be categorized as specific or non-specific, and for each disease type, causation can be proven by different types of evidence. However, the concept of specific diseases is not compatible with multifactor theory, which is generally accepted in the field of public health. Second, when the epidemiological association between the disease and the risk factor is proven to be significant, imposing additional burdens of proof on the plaintiff may considerably limit the plaintiff's right to recovery, but the Court required the plaintiffs to provide additional information such as health condition and lifestyle. Third, the Supreme Court is not giving greater weight to the evidential value of epidemiological study results because the Court focuses on the fact that these studies were group-level, not individual-level. However, group-level studies could still offer valuable information about individual members of the group, e.g., probability of causation.


Assuntos
Responsabilidade Legal , Fumar , Cloracne/epidemiologia , Cloracne/etiologia , Humanos , Estilo de Vida , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Saúde Pública , República da Coreia , Fatores de Risco , Fumar/efeitos adversos
7.
Biochem Pharmacol ; 112: 1-5, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-26801687

RESUMO

Target cells and molecular targets responsible for dioxin-mediated chloracne, the hallmark of dioxin toxicity, are reviewed. The dioxin TCDD accumulates in sebum, and thereby persistently activates the Ah receptor (AhR), expressed in bipotential stem/progenitor cells of the sebaceous gland. AhR operates in cooperation with other transcription factors including c-Myc, Blimp1 and ß-Catenin/TCF: c-Myc stimulates exit of stem cells from quiescence to proliferating sebocyte progenitors; Blimp1 is a major c-Myc repressor, and ß-Catenin/TCF represses sebaceous gland differentiation and stimulates differentiation to interfollicular epidermis. TCDD has been demonstrated to induce Blimp1 expression in the sebocyte stem/progenitor cell line SZ95, leading to sebocyte apoptosis and proliferation of interfollicular epidermis cells. These findings explain observations in TCDD-poisoned individuals, and identify target cells and molecular targets of dioxin-mediated chloracne. They clearly demonstrate that the AhR operates in a cell context-dependent manner, and provide hints to homeostatic functions of AhR in stem/progenitor cells.


Assuntos
Cloracne/etiologia , Dioxinas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cloracne/metabolismo , Cloracne/patologia , Dioxinas/farmacocinética , Humanos , Glândulas Sebáceas/efeitos dos fármacos , Glândulas Sebáceas/metabolismo , Glândulas Sebáceas/patologia , Sebo/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Células-Tronco/patologia
9.
Dermatology ; 231(4): 334-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26440531

RESUMO

BACKGROUND: Dioxins are persistent organic pollutants present in the environment. They exert their biological effects by binding to an intracellular receptor, the aryl hydrocarbon receptor (AhR). Activation of AhR leads to the induction of cytochrome p450 1A1 (CYP1A1). Expression of CYP1A1 in human skin is a key marker for AhR activation, and it may induce comedogenesis resulting in acne-like lesions known as chloracne/metabolising acquired dioxin-induced skin hamartomas (MADISH). The contribution of this pathway in patients seen in a busy acne clinic is unknown. MATERIALS AND METHODS: We explored the expression of CYP1A1 by immunohistochemistry in the acne lesions of 16 patients living in the region of Naples, Italy, where epidemiological studies have suggested a possibly increased exposure to environmental dioxins. A composite score to outline potential components of the chloracne/MADISH histological pattern was used. RESULTS: CYP1A1 expression was observed in 11 lesions (69%) and was distributed in sebaceous glands, follicular epithelium, cystic wall and endothelial cells. The histological score for chloracne/MADISH was 'likely' in 3 cases and 'possible' in 11 cases. Compared to current data on CYP1A1 expression in the skin of 67 patients with proven exposure to AhR agonists, these data indicate a high incidence of AhR activation in this series. CONCLUSION: This is the first study analysing AhR activation in skin in a series of patients from a hospital-based acne clinic. It provides information for future controlled prospective studies. The significance of CYP1A1 expression in terms of AhR ligand exposure is discussed.


Assuntos
Acne Vulgar/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Dioxinas , Exposição Ambiental , Receptores de Hidrocarboneto Arílico/metabolismo , Acne Vulgar/patologia , Cloracne/patologia , Dioxinas/metabolismo , Dioxinas/toxicidade , Células Endoteliais/química , Exposição Ambiental/efeitos adversos , Cisto Epidérmico/metabolismo , Cisto Epidérmico/patologia , Folículo Piloso/química , Humanos , Imuno-Histoquímica , Itália , Estudos Prospectivos , Glândulas Sebáceas/química
10.
Dermatology ; 231(4): 322-5, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26360246

RESUMO

Many environmental acne disorders, including chloracne and oil acne, were previously thought to occur predominantly in occupational settings following polycyclic aromatic hydrocarbon exposure. Cigarette smoke has also been shown to contain a large number of these toxic polycyclic aromatic hydrocarbon components and strictly correlates with noninflammatory acneiform lesion development in postadolescent patients. We report a case of localized open comedones associated with occluded cigarette smoke exposure near the nasal cavity due to infrequently changed gauze following rhinectomy. The dermal uptake of polycyclic aromatic hydrocarbon components in cigarette smoke has the potential to function as a contributing factor in chloracne development. Several of these environmental and noninflammatory acne subtypes may share a common molecular propensity for enhanced comedogenesis originating from aryl hydrocarbon receptor pathway effects in the skin. Additional studies are needed to further elucidate the exact mechanistic pathways through which tobacco smoke impacts the integumentary system.


Assuntos
Cloracne/etiologia , Dermatoses Faciais/etiologia , Fumaça/efeitos adversos , Produtos do Tabaco/efeitos adversos , Animais , Bandagens , Humanos , Masculino , Pessoa de Meia-Idade , Nariz/cirurgia
12.
Med Hypotheses ; 84(3): 204-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25618441

RESUMO

The environmental toxin 2,3,7,8 tetrachlorodibenzo p-dioxin (TCDD) plays an important role in the development of chloracne. Chloracne is characterized by hyperkeratosis of the interfollicular squamous epithelium and metaplasia of sebaceous glands. Dysregulation of keratinocyte terminal differentiation leading to accelerated formation of the cornified envelope as a result of TCDD-mediated aryl hydrocarbon receptor (AHR) activation has been implicated as one of the molecular pathogenic mechanisms contributing to the development of chloracne. In addition, chloracne is characterized by altered skin stem cell characteristics, and it has been speculated that the phenotype of chloracne closely matches that of c-Myc overexpressing transgenic mice. Therefore, we sought to determine whether TCDD plays a role in regulation of the skin stem cell population. We have proposed in this report that TCDD may directly or indirectly (via AHR receptor cross-talk) upregulate c-Myc via epidermal growth factor receptor-extracellular signal regulated kinase (EGFR-ERK) axis stimulation, which may correspond with an increase in human epidermal stem cell activation and differentiation of EPSCs into keratinocytes, with eventual depletion of the epidermal stem cell compartment of the skin. Thus, TCDD may cause increased epidermal stem cell turnover during chloracne.


Assuntos
Diferenciação Celular/fisiologia , Cloracne/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/citologia , Células-Tronco/fisiologia , Receptores ErbB/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pele/patologia , Células-Tronco/metabolismo
13.
EMBO Mol Med ; 6(4): 431-3, 2014 04.
Artigo em Inglês | MEDLINE | ID: mdl-24521743

RESUMO

The nuclear factor erythroid 2-related factor 2 (Nrf2) is best known for its role in resistance to oxidant stress. In this issue of EMBO Molecular Medicine, Nrf2-prolonged genetic activation is shown with devastating effects on skin homeostasis. The study provides novel molecular insights into poison-induced chloracne and metabolizing acquired dioxin-induced skin hamartomas or MADISH.


Assuntos
Cloracne/metabolismo , Queratinócitos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Humanos
14.
EMBO Mol Med ; 6(4): 442-57, 2014 04.
Artigo em Inglês | MEDLINE | ID: mdl-24503019

RESUMO

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/"metabolizing acquired dioxin-induced skin hamartomas" (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.


Assuntos
Cloracne/metabolismo , Queratinócitos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Células Cultivadas , Cloracne/genética , Modelos Animais de Doenças , Epigen/genética , Epigen/metabolismo , Folículo Piloso/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/genética , Inibidor Secretado de Peptidases Leucocitárias/genética , Inibidor Secretado de Peptidases Leucocitárias/metabolismo
15.
Int Arch Occup Environ Health ; 87(2): 125-35, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23292295

RESUMO

OBJECTIVES: After cargo with PCB-containing transformer oil waste was damaged in heavy seas, the vessel crew exposed to PCB developed itching and acne-form eruption of the skin. The objective of our study was to analyse this work-related incident and its effects on health. METHODS: Air and wipe test samples were taken in the ship for analysis of PCB (28/52/101/138/153/180); clinical investigations of all seafarers (n = 6) included lung function, chest X-ray, clinical chemistry and biomonitoring (plasma PCBs, chlorophenols in urine) measured after a latency of 7 weeks. The biomonitoring data were adjusted according to age-related reference values and validated against controls (n = 96). RESULTS: Biomonitoring showed elevated PCB-28-/52/-102/-138 congeners (mean 1.16/0.91/136, ∑PCB: 5.82 µg/l), which correlates with the dust samples from the cargo hold (∑PCB. 9,440 mg/m(2)) and with 6.1 and 5.0 µg/m(3) in stern and bow cargo air samples. IgE elevation in two seafarers and substantial blood sedimentation rate increase with anaemia or pulmonary emphysema were unlikely to be caused by PCB exposure. Although two members showed slightly elevated airway resistance values, other lung function parameters were normal and reactive airways dysfunction syndrome due to PCBs could be excluded. Elevated chlorophenols in urine could contribute to the manifestation of chloracne. CONCLUSIONS: PCB-52/-101/-138 found in plasma and in air samples confirm exposure to PCB. Acne-form skin eruptions were from occupational exposure to polychlorinated biphenyls in the spilt transformer oil. There were no other abnormal findings in medical and clinical examinations that could be attributed to PCBs. This does not exclude possible long-term effects.


Assuntos
Exposição Ocupacional/análise , Bifenilos Policlorados/análise , Navios , Adulto , Poluentes Ocupacionais do Ar/efeitos adversos , Poluentes Ocupacionais do Ar/análise , Estudos de Casos e Controles , Cloracne/etiologia , Clorofenóis/urina , Poeira/análise , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Oceanos e Mares , Bifenilos Policlorados/efeitos adversos , Bifenilos Policlorados/sangue , Radiografia , Testes de Função Respiratória
16.
J Dermatol Sci ; 73(1): 10-22, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24161567

RESUMO

BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent activator of the aryl hydrocarbon receptor (AhR) and causes chloracne in humans. The pathogenesis and role of AhR in chloracne remains incompletely understood. OBJECTIVE: To elucidate the mechanisms contributing to the development of the chloracne-like phenotype in a human epidermal equivalent model and identify potential biomarkers. METHODS: Using primary normal human epidermal keratinocytes (NHEK), we studied AhR activation by XRE-luciferase, AhR degradation and CYP1A1 induction. We treated epidermal equivalents with high affinity TCDD or two non-chloracnegens: ß-naphthoflavone (ß-NF) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Using Western blotting and immunochemistry for filaggrin (FLG), involucrin (INV) and transglutaminase-1 (TGM-1), we compared the effects of the ligands on keratinocyte differentiation and development of the chloracne-like phenotype by H&E. RESULTS: In NHEKs, activation of an XRE-luciferase and CYP1A1 protein induction correlated with ligand binding affinity: TCDD>ß-NF>ITE. AhR degradation was induced by all ligands. In epidermal equivalents, TCDD induced a chloracne-like phenotype, whereas ß-NF or ITE did not. All three ligands induced involucrin and TGM-1 protein expression in epidermal equivalents whereas FLG protein expression decreased following treatment with TCDD and ß-NF. Inhibition of AhR by α-NF blocked TCDD-induced AhR activation in NHEKs and blocked phenotypic changes in epidermal equivalents; however, AhR knock down did not reproduce the phenotype. CONCLUSION: Ligand-induced CYP1A1 and AhR degradation did not correlate with their chloracnegenic potential, indicating that neither CYP1A1 nor AhR are suitable biomarkers. Mechanistic studies showed that the TCDD-induced chloracne-like phenotype depends on AhR activation whereas AhR knock down did not appear sufficient to induce the phenotype.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Cloracne/etiologia , Epiderme/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Queratinócitos/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Cloracne/genética , Cloracne/metabolismo , Cloracne/patologia , Citocromo P-450 CYP1A1/biossíntese , Relação Dose-Resposta a Droga , Indução Enzimática , Epiderme/metabolismo , Epiderme/patologia , Humanos , Indóis/toxicidade , Proteínas de Filamentos Intermediários/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Ligantes , Fenótipo , Precursores de Proteínas/metabolismo , Interferência de RNA , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Tiazóis/toxicidade , Transfecção , Transglutaminases/metabolismo , beta-Naftoflavona/toxicidade
17.
Toxicol Lett ; 230(2): 225-33, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24239782

RESUMO

Dioxins are a family of molecules associated to several industrial accidents such as Ludwigshafen in 1953 or Seveso in 1976, to the Agent Orange used during the war of Vietnam, and more recently to the poisoning of the former president of Ukraine, Victor Yushchenko. These persistent organic pollutants are by-products of industrial activity and bind to an intracellular receptor, AhR, with a high potency. In humans, exposure to dioxins, in particular 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces a cutaneous syndrome known as chloracne, consisting in the development of many small skin lesions (hamartoma), lasting for 2-5 years. Although TCDD has been classified by the WHO as a human carcinogen, its carcinogenic potential to humans is not clearly demonstrated. It was first believed that AhR activation accounted for most, if not all, biological properties of dioxins. However, certain AhR agonists found in vegetables do not induce chloracne, and other chemicals, in particular certain therapeutic agents, may induce a chloracne-like syndrome without activating AhR. It is time to rethink the mechanism of dioxin toxicity and analyse in more details the biological events following exposure to these compounds and other AhR agonists, some of which have a very different chemical structure than TCDD. In particular various food-containing AhR agonists are non-toxic and may on the contrary have beneficial properties to human health.


Assuntos
Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Cloracne/etiologia , Humanos , Neoplasias/induzido quimicamente , Receptores de Hidrocarboneto Arílico/fisiologia , Reprodução/efeitos dos fármacos , Pele/efeitos dos fármacos
18.
J Drugs Dermatol ; 10(11): 1331-4, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22052319

RESUMO

Sorafenib is a chemotherapeutic agent primarily used to treat metastatic renal cell carcinoma. It is a multikinase inhibitor that blocks cell proliferation and angiogenesis. Numerous cutaneous side effects have been reported in association with this medication, including acral erythema, inflammation of actinic keratoses, erythema multiforme, vasculitis, and keratoacanthomas. Up to 40 percent of patients on this medication develop dermatologic manifestations. We describe chloracne-like eruptions in two different patients with no exposure to aromatic hydrocarbons but who were recently started on sorafenib for treatment of metastatic renal carcinoma. The primary reason for discontinuation of sorafenib is secondary to its adverse side effect profile. Recognizing these effects early and administering appropriate treatment will likely increase medication compliance and minimize both dose reductions and discontinuation of the medication resulting in optimal treatment outcomes.


Assuntos
Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Erupção por Droga/etiologia , Piridinas/efeitos adversos , Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Cloracne/etiologia , Cloracne/patologia , Erupção por Droga/patologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/uso terapêutico , Sorafenibe
19.
Toxicol Lett ; 201(3): 230-4, 2011 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-21237254

RESUMO

OBJECTIVE: Chloracne is one of the most sensitive and specific hallmark of dioxin intoxication. Although its clinical features are clearly described, poor understanding of the molecular pathways of dioxin-induced chloracne hampers a rational approach to therapy. The aim of the present study was to investigate the role of EGFR, MAPK, CK17, and TGk in the pathogenesis of chloracne related to dioxin exposures. METHODS: Epidermal tissues of twelve chloracne patients exposed to dioxins were compared with tissues from 12 healthy controls. These skin tissues were obtained by punch biopsies. p-EGFR and p-MAPK were examined by immunofluorescence. The mRNA and protein levels of CK17 and TGk were examined by fluorescence in situ hybridization and immunohistochemistry, respectively. RESULTS: p-EGFR and p-MAPK were found in all chloracne tissues, whereas no expression was found in the controls. CK17 mRNA and protein were also found in all chloracne lesions, but none in controls (P=0.000). TGk mRNA and protein were detected in both groups, but the distribution was distinct. The positive signals in the controls were mainly in the stratum granulosum, while in the chloracne tissues, the positive signals were found more significantly in the stratum granulosum and stratum spinosum. CONCLUSIONS: The results demonstrate that in the human skin the activation of mitogen-activated protein kinase pathway and up-regulation of CK17 and TGK may play roles in the pathogenesis of chloracne related to dioxin exposures.


Assuntos
Cloracne/metabolismo , Dioxinas/toxicidade , Receptores ErbB/biossíntese , Queratina-17/biossíntese , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Pele/metabolismo , Transglutaminases/biossíntese , Consumo de Bebidas Alcoólicas/metabolismo , Epiderme/metabolismo , Receptores ErbB/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Queratina-17/genética , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/genética , Exposição Ocupacional , Pele/enzimologia , Fumar/metabolismo , Transglutaminases/genética
20.
Toxicol Pathol ; 39(1): 240-66, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21177527

RESUMO

The 2010 annual National Toxicology Program (NTP) Satellite Symposium, entitled "Pathology Potpourri," was held in Chicago, Illinois, in advance of the scientific symposium sponsored jointly by the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). The goal of the annual NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for voting or discussion. Some topics covered during the symposium included a comparison of rat and mouse hepatocholangiocarcinoma, a comparison of cholangiofibrosis and cholangiocarcinoma in rats, a mixed pancreatic neoplasm with acinar and islet cell components, an unusual preputial gland tumor, renal hyaline glomerulopathy in rats and mice, eosinophilic substance in the nasal septum of mice, INHAND nomenclature for proliferative and nonproliferative lesions of the CNS/PNS, retinal gliosis in a rat, fibroadnexal hamartoma in rats, intramural plaque in a mouse, a treatment-related chloracne-like lesion in mice, and an overview of mouse ovarian tumors.


Assuntos
Neoplasias/patologia , Terminologia como Assunto , Toxicologia , Animais , Axônios/patologia , Carcinoma de Células Acinares/patologia , Carcinoma de Células das Ilhotas Pancreáticas/patologia , Cloracne/patologia , Colangiocarcinoma/patologia , Congressos como Assunto , Ependimoma/patologia , Camundongos , Degeneração Neural/patologia , Neoplasias Pancreáticas/patologia , Ratos
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