Global alteration of gene expression in human keratinocytes by inorganic arsenic

Area of Science:

• Environmental toxicology
• Molecular biology
• Dermatology

Background:

• Inorganic arsenic exposure is a global health concern.
• Arsenic's effects on gene expression in skin cells are not fully understood.
• Understanding arsenic's mechanism of action is crucial for risk assessment.

Purpose of the Study:

• To investigate common gene expression alterations in human keratinocytes exposed to inorganic arsenic.
• To elucidate the mechanism of arsenic-induced cellular responses.
• To determine if arsenic affects normal, premalignant, and malignant skin cells similarly.

Main Methods:

• Global gene expression analysis using microarrays on cultured human keratinocytes.
• Treatment with sodium arsenite and arsenate at various concentrations.
• Time-course analysis to observe early and sustained effects.
• Comparison of gene expression changes across different cell types.

Main Results:

• Approximately 30% of 12,000 genes were expressed in keratinocytes.
• Up to 12% of expressed genes showed altered transcription (suppressed more than stimulated) at 2 µM sodium arsenite or 6 µM arsenate.
• Genes involved in reactive oxygen species (ROS) response, notably heme oxygenase-1, were commonly upregulated.
• Sustained ROS generation by arsenicals, unlike transient induction by other agents, was observed.
• Sustained ROS generation correlated with suppressed cellular differentiation.

Conclusions:

• Inorganic arsenic induces widespread, sustained changes in gene expression in human keratinocytes.
• Reactive oxygen species generation appears to be an early and critical event in arsenic's mechanism of action.
• Sustained arsenic-induced ROS may suppress keratinocyte differentiation, potentially contributing to carcinogenesis.
• Findings are relevant to human health at arsenic concentrations found in contaminated drinking water.