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CRISPR screen uncovers SLC26A2 as a modulator of tungsten toxicity in endochondral ossification
Rowa Bakadlag1, Sheena Li2, Cynthia Guilbert2
1Division of Clinical and Translational Research, McGill University, Montreal, Quebec, H4A 3J1, Canada; Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, H3T1E2, Canada.
Abstract:
Tungsten is an emerging environmental contaminant, highlighting the urgent need to elucidate its toxicological characteristics and assess long-term health risks. Our previous investigations show that tungsten deposition in the bone is associated with stalled pre-B lymphocyte differentiation, inhibition of osteogenesis, and increased intervertebral disc degeneration and fibrosis. To delineate the underlying molecular mechanisms, we employed CRISPR-based genomics on NALM-6 cells and identified Solute Carrier Family 26 Member 2 (SLC26A2), a sulfate/chloride antiporter, as a pivotal mediator of tungsten-induced toxicity. SLC26A2 deletion reduced tungsten-induced growth inhibition and intercellular tungsten levels. Functional impairment of SLC26A2 is associated with chondrodysplasias, thus, we hypothesized that tungsten would impair the development of cartilage and bone tissues. Indeed, tungstate exposure impaired chondrogenesis and osteogenesis in murine limb cultures, which was reversible by sulfate supplementation. Our study demonstrates that tungsten exploits SLC26A2 for cellular entry and correlates with bone development disruption through proteoglycan and collagen depletion.
Insights
Tungsten toxicity disrupts bone and cartilage development by exploiting the sulfate transporter SLC26A2. Supplementing sulfate can reverse these harmful effects, offering a potential mitigation strategy for tungsten environmental exposure.
Area of Science:
- Environmental toxicology
- Molecular biology
- Skeletal biology
Background:
- Tungsten is an emerging environmental contaminant with unknown long-term health risks.
- Previous studies link tungsten bone deposition to impaired B-lymphocyte differentiation, osteogenesis, and disc degeneration.
Purpose of the Study:
- To identify molecular mechanisms of tungsten toxicity.
- To investigate the role of Solute Carrier Family 26 Member 2 (SLC26A2) in tungsten uptake and toxicity.
- To assess the impact of tungsten on cartilage and bone development.
Main Methods:
- CRISPR-based genomics in NALM-6 cells to identify key mediators of tungsten toxicity.
- Murine limb organ cultures exposed to tungstate.
- Assessment of chondrogenesis and osteogenesis.
- Analysis of proteoglycan and collagen levels.
Main Results:
- SLC26A2 was identified as a critical mediator of tungsten-induced toxicity.
- SLC26A2 deletion reduced cellular tungsten uptake and toxicity.
- Tungstate exposure impaired chondrogenesis and osteogenesis in murine limb cultures.
- Sulfate supplementation reversed tungstate-induced developmental defects.
- Tungsten exposure led to proteoglycan and collagen depletion.
Conclusions:
- Tungsten enters cells via SLC26A2, mediating its toxicity.
- Tungsten disrupts skeletal development, specifically cartilage and bone formation.
- Sulfate availability is crucial for mitigating tungsten's adverse effects on bone and cartilage development.
