Hexavalent chromium disrupts chromatin architecture

Abstract

Accessibility of DNA elements and the orchestration of spatiotemporal chromatin-chromatin interactions are critical mechanisms in the regulation of gene transcription. Thus, in an ever-changing milieu, cells mount an adaptive response to environmental stimuli by modulating gene expression that is orchestrated by coordinated changes in chromatin architecture. Correspondingly, agents that alter chromatin structure directly impact transcriptional programs in cells. Heavy metals, including hexavalent chromium (Cr(VI)), are of special interest because of their ability to interact directly with cellular protein, DNA and other macromolecules, resulting in general damage or altered function. In this review we highlight the chromium-mediated mechanisms that promote disruption of chromatin architecture and how these processes are integral to its carcinogenic properties. Emerging evidence shows that Cr(VI) targets nucleosomal architecture in euchromatin, particularly in genomic locations flanking binding sites of the essential transcription factors CTCF and AP1. Ultimately, these changes contribute to an altered chromatin state in critical gene regulatory regions, which disrupts gene transcription in functionally relevant biological processes.

Introduction

Chromium is an abundant transition metal that is most commonly found in the environment as one of three stable valences, as either trivalent (Cr(III)), hexavalent (Cr(VI)) or metallic (Cr(0). While Cr(III) is the most common form that occurs naturally, the origins of Cr(VI) compounds can largely be attributed to anthropogenic sources due to the industrial use of chromium products in stainless-steel production, electroplating, leather tanning, textile and pigment production, among others [1]. Trivalent chromium can be harmful in acute exposures, however the hexavalent form is considered to be substantially more toxic on account of its increased ability to cross cellular membranes. On the other hand, Cr(III) relies on passive diffusion to permeate the cell membrane, substantially limiting its accumulation within cells. While Cr(VI) is largely reduced in the extracellular environment to Cr(III), molecules that escape the initial detoxification process are rapidly facilitated into the cell through nonspecific sulfate/phosphate anion transporters and subsequently reduced to Cr(III) by ascorbate, glutathione, and to a lesser extent cysteine, through one- or two- step reductions (depending on the reducing agent) [[2], [3], [4], [5], [6]].

Consequently, studies investigating the toxicity of chromium largely focus on the hexavalent species. Specifically, Cr(VI) has been well-established as a respiratory carcinogen through multiple epidemiological and animal studies, with an emphasis on occupational settings where chromate workers are primarily exposed through inhalation and dermal contact. However, the most common route of exposure for the general population is the ingestion of drinking water contaminated with low levels Cr(VI) which may be the result of improper disposal methods of chromium waste, pollution, and natural sources. A recent study by Tan et al. has reported that interactions between cast iron pipes and chlorine disinfectants in drinking water distribution systems can promote the formation of Cr(VI) [7]. While evidence suggesting ingestion is associated with increased cancer incidence exists, the quantification of risk in the general population is not as clear. Despite this, current models of Cr(VI) uptake and intracellular metabolism suggest that carcinogenesis is inextricably linked to the molecular properties of chromium and further understanding the mechanisms through which chromium promotes carcinogenesis is important for improving the health and safety of the population. Continued advances in our understanding of the genome highlight the critical role chromatin organization plays in the function of the cell. Based on current evidence, chromium interferes with the structure and function at multiple levels of chromatin compaction. By damaging DNA directly, through the formation of DNA adducts and protein-DNA crosslinks, Cr(VI) evokes a DNA damage response that requires extensive chromatin remodeling to accommodate the repair machinery [8,9]. At the nucleosome level, emerging evidence is showing that Cr(VI) alters chromatin accessibility by changing the nucleosomal occupancy and positional shifts [10]. Importantly, these changes occur at CTCF and AP1 binding sites, supporting a mechanism where Cr(VI) alters the DNA binding capacities of critical transcription factors, leading to an altered chromatin state. Ultimately, Cr(VI) targets active gene regulatory regions, disrupting gene transcription in biologically relevant cellular processes.