RESUMEN
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.
Asunto(s)
Antineoplásicos/efectos adversos , Cloracné/patología , Quiste Epidérmico/metabolismo , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Vemurafenib/efectos adversos , Antineoplásicos/farmacología , Cloracné/etiología , Cloracné/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Dioxinas/efectos adversos , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/metabolismo , Erupciones por Medicamentos/patología , Activación Enzimática/efectos de los fármacos , Quiste Epidérmico/inducido químicamente , Clorhidrato de Erlotinib/farmacología , Femenino , Gefitinib/farmacología , Células Hep G2 , Humanos , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Vemurafenib/farmacologíaRESUMEN
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.
Asunto(s)
Agricultura , Cloracné/etiología , Dermatitis Profesional/etiología , Exposición Profesional/efectos adversos , Plaguicidas/efectos adversos , Niño , Cloracné/patología , Dermatitis Profesional/patología , Familia , Humanos , MasculinoRESUMEN
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.
Asunto(s)
Cloracné/etiología , Dioxinas/toxicidad , Receptores de Hidrocarburo de Aril/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Cloracné/metabolismo , Cloracné/patología , Dioxinas/farmacocinética , Humanos , Glándulas Sebáceas/efectos de los fármacos , Glándulas Sebáceas/metabolismo , Glándulas Sebáceas/patología , Sebo/metabolismo , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Células Madre/patologíaRESUMEN
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.
Asunto(s)
Acné Vulgar/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Dioxinas , Exposición a Riesgos Ambientales , Receptores de Hidrocarburo de Aril/metabolismo , Acné Vulgar/patología , Cloracné/patología , Dioxinas/metabolismo , Dioxinas/toxicidad , Células Endoteliales/química , Exposición a Riesgos Ambientales/efectos adversos , Quiste Epidérmico/metabolismo , Quiste Epidérmico/patología , Folículo Piloso/química , Humanos , Inmunohistoquímica , Italia , Estudios Prospectivos , Glándulas Sebáceas/químicaRESUMEN
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.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Cloracné/etiología , Epidermis/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Queratinocitos/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Cloracné/genética , Cloracné/metabolismo , Cloracné/patología , Citocromo P-450 CYP1A1/biosíntesis , Relación Dosis-Respuesta a Droga , Inducción Enzimática , Epidermis/metabolismo , Epidermis/patología , Proteínas Filagrina , Humanos , Indoles/toxicidad , Proteínas de Filamentos Intermediarios/metabolismo , Queratinocitos/metabolismo , Queratinocitos/patología , Ligandos , Fenotipo , Precursores de Proteínas/metabolismo , Interferencia de ARN , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Tiazoles/toxicidad , Transfección , Transglutaminasas/metabolismo , beta-naftoflavona/toxicidadRESUMEN
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.
Asunto(s)
Antineoplásicos/efectos adversos , Bencenosulfonatos/efectos adversos , Erupciones por Medicamentos/etiología , Piridinas/efectos adversos , Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Cloracné/etiología , Cloracné/patología , Erupciones por Medicamentos/patología , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/uso terapéutico , SorafenibRESUMEN
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.
Asunto(s)
Neoplasias/patología , Terminología como Asunto , Toxicología , Animales , Axones/patología , Carcinoma de Células Acinares/patología , Carcinoma de Células de los Islotes Pancreáticos/patología , Cloracné/patología , Colangiocarcinoma/patología , Congresos como Asunto , Ependimoma/patología , Ratones , Degeneración Nerviosa/patología , Neoplasias Pancreáticas/patología , RatasRESUMEN
Chloracne, first described by Herxheimer in 1899, is a dermatosis consisting of more or less diffuse acneiform lesions distributed prevalently on the face and on body areas not usually affected by acne and caused by chronic or acute exposure to halogenated chemical compounds. Dioxin is the common name for dibenzo-p-dioxins and dibenzofurans, contaminants nearly ubiquitous in the environment and highly resistant to chemical and biological degradation. These compounds can survive for decades in the environment and accumulate in the human and animal food chains. Chloracne is characterized by the onset of numerous comedo-like lesions and yellowish cysts on the face, particularly on the cheeks, that can spread to the trunk and other body regions not usually affected by acne vulgaris, with diffuse grayish skin pigmentation and sometimes associated with hypertrichosis and areas of folliculitis. The lesions may occasionally be accompanied by skin or systemic manifestations. We report 9 cases of chloracne, 8 of them with rapid onset in patients residing in the same building, and 1 in a patient occupationally exposed to halogenated compounds. In our series, the doses of dioxin and polychlorinated biphenyls in the soil, water and plant material, and the serum titer of dioxin were within the normal range. This consideration raises the issue of the need to revise the serum threshold for dioxin poisoning and the environmental threshold. We wish also to underline the value of dermatopathology in the differential diagnosis of chloracne.
Asunto(s)
Benzofuranos/toxicidad , Cloracné/etiología , Cloracné/patología , Dioxinas/toxicidad , Anciano , Anciano de 80 o más Años , Cloracné/sangre , Dioxinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
Exposure to dioxin and dioxin-like compounds (DLCs) has been connected to the induction of chloracne in humans and animals. 3,3',4,4'-Tetrachloroazobenzene (TCAB) is an environmental contaminant that induces chloracne in humans. TCAB has been studied only to a limited extent in laboratory animals. While performing a 2-year gavage study in B6C3F1 mice to evaluate the toxic and carcinogenic effects of TCAB, we also explored potential chloracnegenic properties. Groups of 50 male and 50 female B6C3F1 mice were exposed by gavage to TCAB at dose levels of 0, 3, 10 and 30 mg/kg for 5 days a week for 2 years. The animals developed treatment-related gross inflammatory skin lesions, which were characterized histologically by inflammation, fibrosis, hyperplasia, and ulcers. Additionally, many of the animals developed follicular dilatation and sebaceous gland atrophy, consistent with chloracne-like lesions. This current 2-year study supports recently published papers showing susceptibility to chloracne in mouse strains other than hairless mice. The chloracne-like lesions were not clinically evident; therefore, our study highlights the need for careful examination of the skin in order to identify subtle lesions consistent with chloracne-like changes in rodents exposed to dioxin and DLCs. Since previous short-term studies did not demonstrate any skin lesions, we suggest that reliable assessment of all safety issues involving dioxin and DLCs requires evaluation following chronic exposure. Such studies in animal models will help to elucidate the mechanisms of dioxin-related health hazards.
Asunto(s)
Compuestos Azo/toxicidad , Cloracné/patología , Clorobencenos/toxicidad , Dermatitis por Contacto/patología , Piel/patología , Animales , Femenino , Intubación Gastrointestinal , Masculino , Ratones , Ratones Endogámicos , Caracteres Sexuales , Análisis de SupervivenciaRESUMEN
Chloracne is an acneiform eruption caused though poisoning by aromatic compounds (usually halogenated) showing a specific molecular configuration. We describe an outbreak of chloracne among seven discovery chemists who synthesized novel polycyclic halogenated chemical compounds which were classified as triazoloquinoxalines, not known to be chloracnegenic. The diagnosis of chloracne, made clinically, elicited a thorough risk assessment and monitoring programme by the occupational health department. The chemists were investigated by serum excretion rates, skin sampling for Propionibacterium acnes, skin biopsy and laboratory blood investigations. Sebum excretion was normal in five cases, raised in one case and severely reduced in another. Skin levels of P. acnes were normal in all patients except for the one subject who had low sebum excretion, in whom they were undetectable. One subject had a slightly raised serum level of alanine aminotransferase. There were no other signs of systemic toxicity. Two subjects were treated with an oral antibiotic, two received topical therapy only and three required no treatment at all. The patients have had thorough health surveillance at 6-monthly and yearly intervals. In each case the chloracne mostly resolved within 18-24 months although on examination about 3 years later, five of the seven still showed minor changes of chloracne. This outbreak emphasizes the need for vigilance in discovery science. The triazoloquinoxalines were not previously recognized as being chloracnegens although their chemical characteristics were subsequently identified as being in keeping with other chemicals that can cause chloracne. Chloracne can be a difficult diagnosis to make when it occurs in a novel setting: occupational physicians and dermatologists need to be vigilant when dealing with unusual eruptions in discovery chemists.