Exposure to Nickel, Chromium, or Cadmium Causes Distinct Changes in the Gene Expression Patterns of a Rat Liver Derived Cell Line

Matthew G Permenter,John A Lewis,David A Jackson,Michael Polymenis

doi:10.1371/journal.pone.0027730

Matthew G Permenter, John A Lewis + Show 2 more

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https://doi.org/10.1371/journal.pone.0027730

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Abstract

Many heavy metals, including nickel (Ni), cadmium (Cd), and chromium (Cr) are toxic industrial chemicals with an exposure risk in both occupational and environmental settings that may cause harmful outcomes. While these substances are known to produce adverse health effects leading to disease or health problems, the detailed mechanisms remain unclear. To elucidate the processes involved in the toxicity of nickel, cadmium, and chromium at the molecular level and to perform a comparative analysis, H4-II-E-C3 rat liver-derived cell lines were treated with soluble salts of each metal using concentrations derived from viability assays, and gene expression patterns were determined with DNA microarrays. We identified both common and unique biological responses to exposure to the three metals. Nickel, cadmium, chromium all induced oxidative stress with both similar and unique genes and pathways responding to this stress. Although all three metals are known to be genotoxic, evidence for DNA damage in our study only exists in response to chromium. Nickel induced a hypoxic response as well as inducing genes involved in chromatin structure, perhaps by replacing iron in key proteins. Cadmium distinctly perturbed genes related to endoplasmic reticulum stress and invoked the unfolded protein response leading to apoptosis. With these studies, we have completed the first gene expression comparative analysis of nickel, cadmium, and chromium in H4-II-E-C3 cells.

Highlights

Many heavy metals, including nickel, chromium, and cadmium, are widely distributed, posing occupational and environmental exposure risks which may result in adverse health effects
In this work we believe that the induction of Ppp1r15a and damage inducible transcript 3 (Ddit3) is purely related to their role in apoptosis and not indicative of DNA damage. These results suggest that cadmium-induced oxidative stress causes endoplasmic reticulum (ER) stress leading to the unfolded protein response and apoptosis
Nickel, chromium, and cadmium are heavy metals commonly found in industry use and in the environment which have adverse health effects

Summary

Introduction

Many heavy metals, including nickel, chromium, and cadmium, are widely distributed, posing occupational and environmental exposure risks which may result in adverse health effects. Exposure to these metals can occur through contact with contaminated soil, air, water, and food, or by absorption through the skin as a result of manufacturing, pharmaceutical, or industrial processes or environmental contamination. All three metals induce oxidative stress, but nickel and chromium undergo Fenton type reactions forming reactive oxygen species while cadmium is thought to cause oxidative stress through the inhibition of antioxidant enzymes [5,6]. Nickel and cadmium deregulate cell proliferation by perturbing various signaling pathways and transcription factors, possibly through reactive oxygen species, the activation of these pathways is poorly understood [5]

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