Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

Abstract

ᮀTCDD and other polyhalogenated aromatic hydrocarbon ligands of the aryl hydrocarbon receptor (AHR) have been classically considered as non-genotoxic compounds because they fail to be directly mutagenic in either bacteria or most in vitro assay systems. They do so in spite of having repeatedly been linked to oxidative stress and to mutagenic and carcinogenic outcomes. Oxidative stress, on the other hand, has been used as a marker for the toxicity of dioxin and its congeners. We have focused this review on the connection between oxidative stress induction and the toxic effects of fetal and adult dioxin exposure, with emphasis on the large species difference in sensitivity to this agent. We examine the roles that the dioxin-inducible cytochromes P450s play in the cellular and toxicological consequences of dioxin exposure with emphasis on oxidative stress involvement. Many components of the health consequences resulting from dioxin exposure may be attributable to epigenetic mechanisms arising from prolonged reactive oxygen generation.

Dioxin‐Activated AHR: Toxic Responses and the Induction of Oxidative Stress

“…Inactivation of aconitase activity, which is a measure of oxidative stress, occurred in response to TCDD in C57BL/6 mice, but not in resistant DBA/2 mice [4,12]. The studies also showed that iron administration potentiated TCDDinduced toxicity, including hepatic porphyria in C57BL/6 mice, via an oxidative process, but did not do so in the DBA/2 mice.…”

“…Similarly, initial studies concerning the role of ROS and oxidative stress focused primarily on the liver [1, 2, 5, 13-18, 33, 38-41, 52, 97]. These studies clearly demonstrated the roles of lipid peroxidation, DNA damage, production of ROS, altered membrane fluidity, and modulation of glutathione and glutathione metabolizing enzymes in the hepatotoxicty of TCDD and related chemicals [2][3][4]97].…”

“…Various in vivo and in vitro studies were initially conducted by Stohs et al [2,33,34] and subsequently by others [4,35,36] to determine the types of ROS produced in response to TCDD. The results of these studies led to the conclusion that superoxide anion, hydrogen peroxide, and hydroxyl radical were all produced in response to TCDD and other related environmental toxicants.…”

“…The involvement of ROS was greatly expanded upon in subsequent studies emanating from the authors' laboratory and led to the involvement of other laboratories in exploring and assessing the role of oxidative stress in the toxicity of dioxinactivated AHR. The role of oxidative stress in the toxicity of TCDD was initially reviewed by Stohs [2] and subsequently by Dalton et al [3] and Reichard et al [4].…”

Characterisation of transcriptional responses to dioxins and dioxin-like contaminants in roach ( Rutilus rutilus ) using whole transcriptome analysis

“…Several lines of evidence indicate that activation of the AhR might lead to oxidative stress following exposure to DLCs (Reichard et al, 2005;Stohs, 1990). It has been shown that ROS, such as superoxide and hydrogen peroxide, can be generated by the incomplete reduction of O 2 by cytochrome P450 enzymes that are regulated by the AhR (Shertzer et al, 1998).…”