Arsenicals affect base excision repair by several mechanisms

Area of Science:

• Environmental Health
• Toxicology
• Molecular Biology

Background:

• Inorganic arsenic is a known human carcinogen, but its precise mechanisms remain unclear.
• Epigenetic and indirect genotoxic effects, including DNA damage response modulation, are suspected contributors to arsenic carcinogenicity.
• Understanding arsenic metabolism and its impact on DNA repair is crucial for assessing human health risks.

Purpose of the Study:

• To investigate the impact of inorganic arsenic and its metabolites on key base excision repair (BER) players in cultured human lung cells.
• To examine gene expression, protein levels, and protein function (hOGG1) of BER components.
• To compare the effects of arsenite, monomethylarsonic acid (MMA(V)), and dimethylarsinic acid (DMA(V)) on cellular DNA repair.

Main Methods:

• Cultured human lung cells were exposed to inorganic arsenite and its methylated metabolites (MMA(V), DMA(V)).
• Gene expression, protein levels of BER key players (hOGG1, LIGIIIα, XRCC1), and hOGG1 enzyme activity were analyzed.
• Cellular bioavailability and effects at varying arsenic concentrations (≥3.2μM) were assessed.

Main Results:

• Dimethylarsinic acid (DMA(V)) most sensitively affected cellular 8-oxoguanine glycosylase (OGG) activity.
• Arsenite significantly reduced DNA ligase IIIα (LIGIIIα) protein levels.
• Monomethylarsonic acid (MMA(V)) decreased X-ray cross-complementing protein 1 (XRCC1) protein content, with effects observed at lower concentrations than previously reported for DNA damage response.
• Trivalent methylated metabolites showed effects only at cytotoxic concentrations.

Conclusions:

• Inorganic arsenic and its metabolites can disrupt multiple cellular DNA repair pathways.
• The observed effects on BER key players suggest a significant impact on DNA damage response, potentially facilitating arsenic-induced carcinogenicity.
• Mixed arsenic species exposure, common after oral intake, may lead to effective impairment of DNA repair through various mechanisms.