RESUMEN
Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.
Asunto(s)
Disruptores Endocrinos/toxicidad , Trastornos del Desarrollo del Lenguaje/epidemiología , Trastornos del Neurodesarrollo/epidemiología , Efectos Tardíos de la Exposición Prenatal , Transcriptoma/efectos de los fármacos , Animales , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/genética , Encéfalo/efectos de los fármacos , Encéfalo/embriología , Preescolar , Estrógenos/metabolismo , Femenino , Fluorocarburos/análisis , Fluorocarburos/toxicidad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ontología de Genes , Humanos , Locomoción/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Trastornos del Neurodesarrollo/genética , Organoides , Fenoles/análisis , Fenoles/toxicidad , Ácidos Ftálicos/análisis , Ácidos Ftálicos/toxicidad , Embarazo , Medición de Riesgo , Hormonas Tiroideas/metabolismo , Xenopus laevis , Pez CebraRESUMEN
Disruptions in the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases.
