RESUMO
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.
Assuntos
Disruptores Endócrinos/toxicidade , Transtornos do Desenvolvimento da Linguagem/epidemiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Efeitos Tardios da Exposição Pré-Natal , Transcriptoma/efeitos dos fármacos , Animais , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Pré-Escolar , Estrogênios/metabolismo , Feminino , Fluorocarbonos/análise , Fluorocarbonos/toxicidade , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Locomoção/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/genética , Organoides , Fenóis/análise , Fenóis/toxicidade , Ácidos Ftálicos/análise , Ácidos Ftálicos/toxicidade , Gravidez , Medição de Risco , Hormônios Tireóideos/metabolismo , Xenopus laevis , Peixe-ZebraRESUMO
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.