RESUMEN
Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.
Asunto(s)
Trastorno del Espectro Autista , Células Madre Pluripotentes Inducidas , Trastorno del Espectro Autista/genética , Humanos , Neuronas , Proteómica , Transcriptoma/genéticaAsunto(s)
Trastorno del Espectro Autista/patología , Regulación de la Expresión Génica/fisiología , Células Madre Multipotentes/metabolismo , Complejos Multiproteicos/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Androstadienos/farmacología , Estudios de Casos y Controles , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Niño , Medio de Cultivo Libre de Suero/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunosupresores/farmacología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Células Madre Multipotentes/efectos de los fármacos , Fosforilación/efectos de los fármacos , Suero/metabolismo , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Factores de Tiempo , WortmaninaRESUMEN
We assessed the neuropsychological test performances of 26 patients (mean age = 41.5 +/- 6.1 years; mean years of education = 9.8 +/- 1.8; 20 males) diagnosed with chronic occupational mercurialism who were former workers at a fluorescent lamp factory. They had been exposed to elemental mercury for an average of 10.2 +/- 3.8 years and had been away from this work for 6 +/- 4.7 years. Mean urinary mercury concentrations 1 year after cessation of work were 1.8 +/- 0.9 microg/g creatinine. Twenty control subjects matched for age, gender, and education (18 males) were used for comparison. Neuropsychological assessment included attention, inhibitory control, verbal and visual memory, verbal fluency, manual dexterity, visual-spatial function, executive function, and semantic knowledge tests. The Beck Depression Inventory and the State and Trait Inventory were used to assess depression and anxiety symptoms, respectively. The raw score for the group exposed to mercury indicated slower information processing speed, inferior performance in psychomotor speed, verbal spontaneous recall memory, and manual dexterity of the dominant hand and non-dominant hand (P < 0.05). In addition, the patients showed increased depression and anxiety symptoms (P < 0.001). A statistically significant correlation (Pearson) was demonstrable between mean urinary mercury and anxiety trait (r = 0.75, P = 0.03). The neuropsychological performances of the former workers suggest that occupational exposure to elemental mercury has long-term effects on information processing and psychomotor function, with increased depression and anxiety also possibly reflecting the psychosocial context.
Asunto(s)
Exposición por Inhalación/efectos adversos , Trastornos Mentales/inducido químicamente , Trastornos Mentales/etiología , Mercurio/toxicidad , Enfermedades Profesionales/inducido químicamente , Exposición Profesional/efectos adversos , Trastornos Psicomotores/inducido químicamente , Adulto , Atención/efectos de los fármacos , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Memoria/efectos de los fármacos , Trastornos Mentales/diagnóstico , Mercurio/orina , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedades Profesionales/diagnóstico , Trastornos Psicomotores/diagnóstico , Factores de TiempoRESUMEN
We assessed the neuropsychological test performances of 26 patients (mean age = 41.5 ± 6.1 years; mean years of education = 9.8 ± 1.8; 20 males) diagnosed with chronic occupational mercurialism who were former workers at a fluorescent lamp factory. They had been exposed to elemental mercury for an average of 10.2 ± 3.8 years and had been away from this work for 6 ± 4.7 years. Mean urinary mercury concentrations 1 year after cessation of work were 1.8 ± 0.9 æg/g creatinine. Twenty control subjects matched for age, gender, and education (18 males) were used for comparison. Neuropsychological assessment included attention, inhibitory control, verbal and visual memory, verbal fluency, manual dexterity, visual-spatial function, executive function, and semantic knowledge tests. The Beck Depression Inventory and the State and Trait Inventory were used to assess depression and anxiety symptoms, respectively. The raw score for the group exposed to mercury indicated slower information processing speed, inferior performance in psychomotor speed, verbal spontaneous recall memory, and manual dexterity of the dominant hand and non-dominant hand (P < 0.05). In addition, the patients showed increased depression and anxiety symptoms (P < 0.001). A statistically significant correlation (Pearson) was demonstrable between mean urinary mercury and anxiety trait (r = 0.75, P = 0.03). The neuropsychological performances of the former workers suggest that occupational exposure to elemental mercury has long-term effects on information processing and psychomotor function, with increased depression and anxiety also possibly reflecting the psychosocial context.