Vergis, J. | Search bioRxiv

bioRxiv2026

Sex-Specific Modulation of Gene Expression by 17beta-Estradiol in Human Meniscal Cells: Pathways to Targeted Osteoarthritis Therapies

Osteoarthritis (OA) disproportionately affects women, and estrogen has been implicated in cartilage and joint homeostasis, yet its effects on meniscal fibrochondrocytes (MFCs), and whether those effects differ by sex, remain poorly defined. We reanalyzed a publicly available RNA-sequencing dataset (Gene Expression Omnibus, GSE199087) comprising human MFCs from a male and a female donor treated with 17{beta}-estradiol (E2) or vehicle. Differential expression, Gene Set Enrichment Analysis, Enrichr, and iLINCS were integrated to identify the transcriptional programs modulated by E2 in each sex. In female MFCs, E2 upregulated pathways governing DNA replication, cell-cycle progression, and genomic maintenance (e.g., MCM8, BRCA1, RAD51), while downregulating inflammatory and extracellular matrix-degrading genes, including MMP1, IL12A, CXCL12, and MYD88. In male MFCs, E2 instead upregulated chromatin remodeling and developmental signaling programs, led by SRCAP, ERCC6, and NOTCH1, and downregulated antigen presentation and mitochondrial genes. These divergent responses indicate that E2 engages distinct, sex-specific transcriptional programs in MFCs, with the female profile favoring proliferation and matrix preservation. Although derived from a limited sample and therefore hypothesis-generating, these findings nominate candidate mechanisms underlying sex differences in meniscal biology and OA susceptibility, and warrant validation in larger, sex-balanced cohorts. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/740612v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@16026fforg.highwire.dtl.DTLVardef@1a048acorg.highwire.dtl.DTLVardef@3246corg.highwire.dtl.DTLVardef@4c598b_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Folate prevents the autism-related phenotype caused by developmental pyrethroid exposure in prairie voles

Neurodevelopmental disorders (NDDs) have dramatically increased in prevalence to an alarming one in six children, and yet both causes and preventions remain elusive. Recent human epidemiology and animal studies have implicated developmental exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US, as an environmental risk factor for autism and neurodevelopmental disorders. Our previous research has shown that low-dose chronic developmental pyrethroid exposure (DPE) changes folate metabolites in the adult mouse brain. We hypothesize that DPE acts directly on molecular targets in the folate metabolism pathway, and that high-dose maternal folate supplementation can prevent or reduce the biobehavioral effects of DPE. We exposed pregnant prairie vole dams chronically to vehicle or low-dose deltamethrin (3 mg/kg/3 days) with or without high-dose folate supplementation (methylfolate, 5 mg/kg/3 days). The resulting DPE offspring showed broad deficits in five behavioral domains relevant to neurodevelopmental disorders (including the social domain); increased plasma folate concentrations; and increased neural expression of SHMT1, a folate cycle enzyme. Maternal folate supplementation prevented most of the behavioral phenotypes (except for repetitive behaviors) and caused potentially compensatory changes in neural expression of FOLR1 and MTHFR, two folate-related proteins. We conclude that DPE causes neurodevelopmental disorder-relevant behavioral deficits; DPE directly alters aspects of folate metabolism; and preventative interventions targeting folate metabolism are effective in reducing, but not eliminating, the behavioral effects of DPE.

neuroscience↗