RESUMEN
Iraqi born immigrants in Sweden have higher prevalence of metabolic diseases compared to native Swedes. Copeptin, a marker for vasopressin, is associated with increased risk of metabolic disease. In this cross-sectional population study based on the MEDIM cohort we investigated differences in copeptin levels between Iraqi and Swedish born individuals and if the association between copeptin and cardiometabolic risk markers differed by region of origin. We included 1109 Iraqi and 613 Swedish born participants (58% men, mean age 47 years). The Swedish participants had a higher concentration of copeptin compared to the Iraqi born group after age and sex adjustment (p < 0.001). This difference existed only among male individuals with the highest copeptin concentrations, i.e. belonging to copeptin quartile 4 (median (25th; 75th percentile) 20.07 (15.27;33.28) pmol/L for the Swedish born versus 15.57 (13.91;19.00) pmol/L for the Iraqi born, p < 0.001). We found a significant interaction between copeptin (continuous ln-transformed) and being born in Iraq regarding the association with plasma triglycerides (Pinteraction = 0.006). The association between copeptin and BMI was stronger amongst the Iraqi born individuals compared to the Swedish born. Together, this could indicate that copeptin is a more potent marker of metabolic disease among individuals born in Iraq compared to Sweden.
Asunto(s)
Glicopéptidos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Transversales , Suecia/epidemiología , Enfermedades MetabólicasRESUMEN
2,6-Dichlorophenyl methylsulfone (2,6-diClPh-MeSO2) is a potent olfactory toxicant reported to induce endoplasmic reticulum (ER) stress, caspase activation, and extensive cell death in mice. The aim of the present study was to examine cytochrome P450 (P450)-dependent bioactivation, nonprotein sulfhydryl (NP-SH) levels, and early ultrastructural changes in mouse olfactory mucosa following an i.p. injection of 2,6-diClPh-MeSO2 (32 mg/kg). A high covalent binding of 2,6-diClPh-14C-MeSO2 in olfactory mucosa S9 fraction was observed, and the CYP2A5/CYP2G1 substrates coumarin and dichlobenil significantly decreased the binding, whereas the CYP2E1 substrate chlorzoxazone had no effects. An increased bioactivation was detected in liver microsomes of mice pretreated with pyrazole, known to induce CYP2A4, 2A5, 2E1, and 2J, and addition of chlorzoxazone reduced this binding. 2,6-DiClPh-14C-MeSO2 showed a marked covalent binding to microsomes of recombinant yeast cells expressing mouse CYP2A5 or human CYP2A6 compared with wild type. One and 4 h after a single injection of 2,6-diClPh-MeSO2, the NP-SH levels in the olfactory mucosa were significantly reduced compared with control, whereas there was no change in the liver. Ultrastructural studies revealed that ER, mitochondria, and secretory granules in nonneuronal cells were early targets 1 h after injection. We propose that lesions induced by 2,6-diClPh-MeSO2 in the mouse olfactory mucosa were initiated by a P450-mediated bioactivation in the Bowman's glands and depletion of NP-SH levels, leading to disruption of ion homeostasis, organelle swelling, and cell death. The high expression of CYP2A5 in the olfactory mucosa is suggested to play a key role for the tissue-specific toxicity induced by 2,6-diClPh-MeSO2.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/metabolismo , Derivados del Benceno/toxicidad , Oxigenasas de Función Mixta/metabolismo , Mucosa Olfatoria/efectos de los fármacos , Sulfonas/toxicidad , Animales , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Derivados del Benceno/antagonistas & inhibidores , Derivados del Benceno/metabolismo , Clorzoxazona/farmacología , Cumarinas/farmacología , Citocromo P-450 CYP2A6 , Familia 2 del Citocromo P450 , Relación Dosis-Respuesta a Droga , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/ultraestructura , Femenino , Inyecciones Intraperitoneales , Hígado/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Metirapona/farmacología , Ratones , Microscopía Electrónica de Transmisión , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Oxigenasas de Función Mixta/antagonistas & inhibidores , Nitrilos/farmacología , Mucosa Olfatoria/metabolismo , Mucosa Olfatoria/ultraestructura , Pirazoles/farmacología , Compuestos de Sulfhidrilo/metabolismo , Sulfonas/administración & dosificación , Sulfonas/antagonistas & inhibidores , Sulfonas/metabolismoRESUMEN
The potent olfactory toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO(2)) induces rapid cell death and long-term metaplastic changes in the olfactory regions of rodents. The damage is related to a tissue-specific and extensive cytochrome P450 (CYP)-mediated metabolic activation of the compound to reactive intermediates. The aim of the present study was to examine the early, cell-specific changes leading to cell death in the olfactory mucosa of mice exposed to 2,6-diClPh-MeSO(2). We have examined the expression of the ER-specific stress protein GRP78, the presence of secretory glycoproteins, and the cellular activation of the initiator caspase 12 and the downstream effector caspase 3. 2,6-DiClPh-MeSO(2) induced rapid and cell-specific expression of GRP78, and activation of caspases 12 and 3 in the Bowman's glands. No similar early onset changes in the neuroepithelium were observed. Based on these results, we propose that extensive lesions are initiated in the Bowman's glands and that the metabolic activation of 2,6-diClPh-MeSO(2) elicits ER-stress response and subsequent apoptotic signaling at this site. Since most of the Bowman's glands had oncotic morphology, the results suggest that the terminal phase of apoptosis was blocked and that these glands finally succumb to other routes of cell death.
Asunto(s)
Derivados del Benceno/toxicidad , Caspasas/metabolismo , Clorobencenos/toxicidad , Retículo Endoplásmico/efectos de los fármacos , Mucosa Olfatoria/efectos de los fármacos , Animales , Apoptosis , Derivados del Benceno/administración & dosificación , Caspasa 12 , Caspasa 3 , Clorobencenos/administración & dosificación , Retículo Endoplásmico/enzimología , Chaperón BiP del Retículo Endoplásmico , Activación Enzimática/efectos de los fármacos , Femenino , Glicoproteínas/metabolismo , Proteínas de Choque Térmico/metabolismo , Inmunohistoquímica , Ratones , Chaperonas Moleculares/metabolismo , Necrosis , Células Neuroepiteliales/efectos de los fármacos , Células Neuroepiteliales/metabolismo , Células Neuroepiteliales/patología , Mucosa Olfatoria/enzimología , Mucosa Olfatoria/patología , Sulfonas , Factores de TiempoRESUMEN
We performed a detailed analysis of mouse cytochrome P450 2A5 (CYP2A5) expression by in situ hybridization (ISH) and immunohistochemistry (IHC) in the respiratory tissues of mice. The CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region, with an expression in sustentacular cells, Bowman's gland, and duct cells. In the respiratory and transitional epithelium there was no or only weak expression. The nasolacrimal duct and the excretory ducts of nasal and salivary glands displayed expression, whereas no expression occurred in the acini. There was decreasing expression along the epithelial linings of the trachea and lower respiratory tract, whereas no expression occurred in the alveoli. The hepatic CYP2A5 inducers pyrazole and phenobarbital neither changed the CYP2A5 expression pattern nor damaged the olfactory mucosa. In contrast, the olfactory toxicants dichlobenil and methimazole induced characteristic changes. The damaged Bowman's glands displayed no expression, whereas the damaged epithelium expressed the enzyme. The CYP2A5 expression pattern is in accordance with previously reported localization of protein and DNA adducts and the toxicity of some CYP2A5 substrates. This suggests that CYP2A5 is an important determinant for the susceptibility of the nasal and respiratory epithelia to protoxicants and procarcinogens.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/biosíntesis , Contaminantes Ambientales/toxicidad , Oxigenasas de Función Mixta/biosíntesis , Sistema Respiratorio/metabolismo , Animales , Citocromo P-450 CYP2A6 , Familia 2 del Citocromo P450 , Inducción Enzimática , Femenino , Inmunohistoquímica , Hibridación in Situ , Masculino , Metimazol/toxicidad , Ratones , Ratones Endogámicos DBA , Conducto Nasolagrimal/citología , Conducto Nasolagrimal/efectos de los fármacos , Conducto Nasolagrimal/metabolismo , Nitrilos/toxicidad , Mucosa Olfatoria/citología , Mucosa Olfatoria/efectos de los fármacos , Mucosa Olfatoria/metabolismo , Fenobarbital/toxicidad , Pirazoles/toxicidad , Sistema Respiratorio/citología , Sistema Respiratorio/efectos de los fármacos , Glándulas Salivales/citología , Glándulas Salivales/efectos de los fármacos , Glándulas Salivales/metabolismoRESUMEN
This study aimed to explain the isomer- and site-specific toxic effects of dichlorophenyl methylsulphone in the olfactory mucosa of rats. A single ip dose of the 2,6-chlorinated isomer (16 or 65 mg/kg) induced necrosis preferentially in the Bowman's glands and neuroepithelium in the dorsomedial part of the olfactory region. Only minor damage occurred at this site in rats dosed with the 2,5-chlorinated isomer (65 mg/kg). A strong concentration- and time-dependent covalent binding of the (14)C-labeled 2,6-isomer to rat olfactory microsomes was demonstrated. In contrast, no significant covalent binding of the (14)C-labeled 2,5-isomer was observed. The cytochrome P450 (CYP) inhibitors metyrapone, tranylcypromine and acetonitrile inhibited covalent binding of the 2,6-isomer to olfactory microsomes. Glutathione (GSH) appeared to play a protective role as a scavenger of a reactive intermediate whereas methyl-GSH did not alter covalent binding to olfactory microsomes. As determined by microautoradiography, binding of the 2,6-chlorinated isomer in the olfactory mucosa was confined to the Bowman's glands. Both isomers showed a low binding to liver microsomes and caused no liver injury. We suggest that a CYP2A-catalyzed activation of the 2,6-chlorinated dichlorophenyl methylsulphone to a reactive intermediate and adduct formation in the Bowman's glands will initiate a site-specific toxicity of this isomer in the olfactory mucosa.