RÉSUMÉ
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.
Sujet(s)
Perturbateurs endocriniens/toxicité , Troubles du développement du langage/épidémiologie , Troubles du développement neurologique/épidémiologie , Effets différés de l'exposition prénatale à des facteurs de risque , Transcriptome/effets des médicaments et des substances chimiques , Animaux , Trouble du spectre autistique/épidémiologie , Trouble du spectre autistique/génétique , Encéphale/effets des médicaments et des substances chimiques , Encéphale/embryologie , Enfant d'âge préscolaire , Oestrogènes/métabolisme , Femelle , Fluorocarbones/analyse , Fluorocarbones/toxicité , Analyse de profil d'expression de gènes , Régulation de l'expression des gènes , Gene Ontology , Humains , Locomotion/effets des médicaments et des substances chimiques , Cellules souches neurales/effets des médicaments et des substances chimiques , Troubles du développement neurologique/génétique , Organoïdes , Phénols/analyse , Phénols/toxicité , Acides phtaliques/analyse , Acides phtaliques/toxicité , Grossesse , Appréciation des risques , Hormones thyroïdiennes/métabolisme , Xenopus laevis , Danio zébréRÉSUMÉ
The regulation of the proliferation and polarity of neural progenitors is crucial for the development of the brain cortex. Animal studies have implicated glycogen synthase kinase 3 (GSK3) as a pivotal regulator of both proliferation and polarity, yet the functional relevance of its signaling for the unique features of human corticogenesis remains to be elucidated. We harnessed human cortical brain organoids to probe the longitudinal impact of GSK3 inhibition through multiple developmental stages. Chronic GSK3 inhibition increased the proliferation of neural progenitors and caused massive derangement of cortical tissue architecture. Single-cell transcriptome profiling revealed a direct impact on early neurogenesis and uncovered a selective role of GSK3 in the regulation of glutamatergic lineages and outer radial glia output. Our dissection of the GSK3-dependent transcriptional network in human corticogenesis underscores the robustness of the programs determining neuronal identity independent of tissue architecture.
