Biology subjects

Ryan, W. G.

Publications and source records attributed to Ryan, W. G..

3 recordsLinked to original sources

bioRxiv2023

Developmental pyrethroid exposure disrupts molecular pathways for circadian rhythms and synaptic plasticity in mouse brain.

Neurodevelopmental disorders (NDDs) are a category of pervasive disorders of the developing nervous system with few or no recognized biomarkers. A significant portion of the risk for NDDs, including attention deficit hyperactivity disorder (ADHD), is contributed by the environment, and exposure to pyrethroid pesticides during pregnancy has been identified as a potential risk factor for NDD in the unborn child. We recently showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice causes male-biased changes to ADHD- and NDD-relevant behaviors as well as the striatal dopamine system. Here, we used an integrated multiomics approach to determine the broadest possible set of biological changes in the mouse brain caused by developmental pyrethroid exposure (DPE). Using a litter-based, split-sample design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3 mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood, euthanized them, and pulverized and divided whole brain samples for split-sample transcriptomics, kinomics and multiomics integration. Transcriptome analysis revealed alterations to multiple canonical clock genes, and kinome analysis revealed changes in the activity of multiple kinases involved in synaptic plasticity, including the mitogen-activated protein (MAP) kinase ERK. Multiomics integration revealed a dysregulated protein-protein interaction network containing primary clusters for MAP kinase cascades, regulation of apoptosis, and synaptic function. These results demonstrate that DPE causes a multi-modal biophenotype in the brain relevant to ADHD and identifies new potential mechanisms of action. NEW & NOTEWORTHYHere, we provide the first evidence that low-dose developmental exposure to the pyrethroid pesticide, deltamethrin, results in molecular disruptions in the adult mouse brain in pathways regulating circadian rhythms and neuronal growth (MAP kinase). This same exposure causes a neurodevelopmental disorder (NDD) relevant behavioral changes in adult mice, making these findings relevant to the prevention of NDDs.

neuroscience↗

bioRxiv2023

In Silico Transcriptome-based Screens Identify Epidermal Growth Factor Receptor Inhibitors as Therapeutics for Noise-induced Hearing Loss

Noise-Induced Hearing Loss (NIHL) represents a widespread disease for which no therapeutics have been approved by the Food and Drug Administration (FDA). Addressing the conspicuous void of efficacious in vitro or animal models for high throughput pharmacological screening, we utilized an in silico transcriptome-oriented drug screening strategy, unveiling 22 biological pathways and 64 promising small molecule candidates for NIHL protection. Afatinib and zorifertinib, both inhibitors of the Epidermal Growth Factor Receptor (EGFR), were validated for their protective efficacy against NIHL in experimental zebrafish and murine models. This protective effect was further confirmed with EGFR conditional knockout mice and EGF knockdown zebrafish, both demonstrating protection against NIHL. Molecular analysis using Western blot and kinome signaling arrays on adult mouse cochlear lysates unveiled the intricate involvement of several signaling pathways, with particular emphasis on EGFR and its downstream pathways being modulated by noise exposure and Zorifertinib treatment. Administered orally, Zorifertinib was successfully detected in the perilymph fluid of the inner ear in mice with favorable pharmacokinetic attributes. Zorifertinib, in conjunction with AZD5438 - a potent inhibitor of cyclin dependent kinase 2 - produced synergistic protection against NIHL in the zebrafish model. Collectively, our findings underscore the potential application of in silico transcriptome-based drug screening for diseases bereft of efficient screening models and posit EGFR inhibitors as promising therapeutic agents warranting clinical exploration for combatting NIHL. HighlightsO_LIIn silico transcriptome-based drug screens identify pathways and drugs against NIHL. C_LIO_LIEGFR signaling is activated by noise but reduced by zorifertinib in mouse cochleae. C_LIO_LIAfatinib, zorifertinib and EGFR knockout protect against NIHL in mice and zebrafish. C_LIO_LIOrally delivered zorifertinib has inner ear PK and synergizes with a CDK2 inhibitor. C_LI

neuroscience↗

bioRxiv2023

Ribosomal dysregulation: A conserved pathophysiological mechanism in human depression and mouse chronic stress.

The underlying biological mechanisms that contribute to the heterogeneity of major depressive disorder (MDD) presentation remain poorly understood, highlighting the need for a conceptual framework that can explain this variability and bridge the gap between animal models and clinical endpoints. Here, we hypothesize that comparative analysis of molecular data from different experimental systems of chronic stress and MDD has the potential to provide insight into these mechanisms and address this gap. Thus, we compared transcriptomic profiles of brain tissue from postmortem MDD subjects and from mice exposed to chronic variable stress (CVS) to identify orthologous genes. Ribosomal protein genes (RPGs) were downregulated, and associated RP-pseudogenes were upregulated in both conditions. Analysis across independent cohorts confirmed that this dysregulation was specific to the prefrontal cortex of both species. A seeded gene co-expression analysis using altered RPGs common between the MDD and CVS groups revealed that downregulated RPGs homeostatically regulated the synaptic changes in both groups through a RP-pseudogene-driven mechanism. In-vitro and in-silico analysis further demonstrated that the inverse RPG/RP-pseudogene association was a glucocorticoid-driven endocrine response to stress that was reversed during remission from MDD. This study provides the first evidence that ribosomal dysregulation during stress is a conserved phenotype in human MDD and CVS exposed mouse. Our results establish a foundation for the hypothesis that stress-induced alterations in RPGs and, consequently, ribosomes contribute to the synaptic dysregulation underlying MDD and chronic stress-related mood disorders. We discuss a ribosome-dependent mechanism for the variable presentations of depression and other mood disorders. Significance StatementThe presented study highlights the pressing need for a connection between animal models of depression and clinical endpoints. The lack of concordance between these two areas has hindered our understanding of MDDs biological underpinnings. The studys hypothesis that orthologous gene from experimental systems of chronic stress and MDD can bridge this gap is a major advance in this field. The study indicates that dysregulation of ribosomes in the synapse is a common feature in both human MDD and mice exposed to CVS. This dysregulation is a response to endocrine disturbances and is driven by mechanisms that involve pseudogenes. These findings support the hypothesis that stress-induced alterations in RPGs and, consequently, ribosomes may contribute to the variable presentations of depression.

neuroscience↗