Transcriptional profiling reveals ataxia telangiectasia mutated pathways regulate joint copper and arsenic toxicity for hepatic metalloplasia and anti-cancer therapies

Chinnasamy Thirunavukkarasu, Yogeshwar Sharma, Tatyana Tchaikovskaya, Alexander Y. Maslov, Sanjeev Gupta

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Exposures to toxic metals, including arsenic (As), pose health risks but joint effects of physiologically needed metals, e.g., copper (Cu), are ill-defined for regulated metal-dependent cell proliferation (or metalloplasia). This study elucidated hepatic toxicities of As and Cu. Main methods: Human HuH-7 cells were exposed to As and Cu and mRNA profiling obtained for molecular networks, regulators and signaling pathways. This followed biological testing of ATM signaling-related DNA damage response, mitochondrial dysfunction and lysosome activity using HuH-7 cells and primary hepatocytes. Free Cu ions were bound to 3-indole propionic acid for finding their contribution in toxicity. Key findings: The As or As plus Cu toxicities in HuH-7 cells produced dimorphic down- or up-regulation patterns in mRNA profiles. Significant differences extended for ontologies in protein synthesis, intermediary metabolism, mitochondrial function, autophagy, or cell survival and growth. Bioassays revealed ATM signaling regulated As and Cu toxicity for oxidative phosphorylation, mitochondrial membrane potential, lysosomal activity, DNA damage response, and cell growth-arrest. Removal of reactive Cu ions decreased As and Cu toxicity. Primary hepatocytes withstood Cu and As toxicity better. Significance: This joint As and Cu toxicity offers further mechanisms for metalloplasia, carcinogenesis and tissue damage in other settings, e.g., during excess Cu accumulation in Wilson disease. Moreover, joint As and Cu toxicities are relevant for anti-cancer therapies, potentially including manipulations to increase intracellular Cu through altered uptake or efflux processes and incorporating ATM-related checkpoint inhibitors. Superior tolerance of healthy hepatocytes to Cu and As toxicity should improve safety margins for anti-cancer therapies.

Original languageEnglish (US)
Article number120787
JournalLife Sciences
Volume305
DOIs
StatePublished - Sep 15 2022

Keywords

  • DNA damage response
  • Gene regulation
  • Hepatocytes
  • Metals
  • Organelles

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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