ABSTRACT
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.
Subject(s)
Endocrine Disruptors/toxicity , Language Development Disorders/epidemiology , Neurodevelopmental Disorders/epidemiology , Prenatal Exposure Delayed Effects , Transcriptome/drug effects , Animals , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/genetics , Brain/drug effects , Brain/embryology , Child, Preschool , Estrogens/metabolism , Female , Fluorocarbons/analysis , Fluorocarbons/toxicity , Gene Expression Profiling , Gene Expression Regulation , Gene Ontology , Humans , Locomotion/drug effects , Neural Stem Cells/drug effects , Neurodevelopmental Disorders/genetics , Organoids , Phenols/analysis , Phenols/toxicity , Phthalic Acids/analysis , Phthalic Acids/toxicity , Pregnancy , Risk Assessment , Thyroid Hormones/metabolism , Xenopus laevis , ZebrafishABSTRACT
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.
