Eno, A. F. | bioRxiv Science

bioRxiv2026

EpiBrain: the brain's epigenetic landscape in a snapshot

Epigenetics connect nature with nurture and can help explain how genes, experiences, and the environment influence gene expression to promote individual differences in behavior and mental health. However, how these perturbations induce epigenetic changes across various regions of the brain remains largely unknown. To visualize changes in brains epigenetic landscape at a glance, we develop EpiBrain, a method utilizing whole-brain imaging and registration to capture epigenetic changes in the entire zebrafish brain in a snapshot. Using this method, we uncovered brain-wide epigenetic changes induced by brain activity, chemical exposures, and genetic mutations. We found that gadd45b, an immediate early gene with epigenetic modulatory activity, mediates experience-induced epigenetic changes in the brain, and that these changes contribute to brain activity and behavioral alterations. EpiBrain enables rapid and unbiased assessment of whole-brain epigenetic changes following physiological and disease-relevant perturbations and facilitates mechanistic discoveries at the molecular level.

neuroscience↗

bioRxiv2024

Proteome-wide reverse molecular docking reveals folic acid receptor as a mediator of PFAS-induced neurodevelopmental toxicity

Per- and polyfluoroalkyl substances (PFAS) are a class of long-lasting chemicals with widespread use and environmental persistence that have been increasingly studied for their detrimental impacts to human and animal health. Several major PFAS species are linked to neurodevelopmental toxicity. For example, epidemiological studies have associated prenatal exposure to perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) with autism risk. However, the neurodevelopmental toxicities of major PFAS species have not been systematically evaluated in an animal model, and the molecular mechanisms underlying these toxicities have remained elusive. Using a high-throughput zebrafish social behavioral model, we screened six major PFAS species currently under regulation by the Environmental Protection Agency (EPA), including PFOA, PFNA, perfluorooctane sulfonate (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorobutane sulfonate (PFBS), and hexafluoropropylene oxide dimer acid ammonium salt (GenX). We found that embryonic exposure to PFNA, PFOA, and PFOS induced social deficits in zebrafish, recapitulating one of the hallmark behavioral deficits in autistic individuals. To uncover protein targets of the six EPA-regulated PFAS, we screened a virtual library containing predicted binding pockets of over 80% of the 3D human proteome through reverse molecular docking. The screen predicts that folate receptor beta (FR-{beta}, encoded by the gene FOLR2) interacts strongly with PFNA, PFOA, and PFOS but to a lesser degree with PFHxS, PFBS, and GenX, correlating positively with their in vivo toxicity. These predictions were validated through in silico molecular docking, in vitro protein binding analysis, and in vivo loss-of-function verification. Furthermore, embryonic co-exposure to folic acid effectively rescued social deficits induced by PFAS. The folate pathway has been implicated in autism, indicating a novel molecular mechanism for PFAS in autism etiology.

pharmacology and toxicology↗