Redox toxicology of environmental chemicals causing oxidative stress

Abstract

Living organisms are surrounded with heavy metals such as methylmercury, manganese, cobalt, cadmium, arsenic, as well as pesticides such as deltamethrin and paraquat, or atmospheric pollutants such as quinone. Extensive studies have demonstrated a strong link between environmental pollutants and human health. Redox toxicity is proposed as one of the main mechanisms of chemical-induced pathology in humans. Acting as both a sensor of oxidative stress and a positive regulator of antioxidants, the nuclear factor erythroid 2-related factor 2 (NRF2) has attracted recent attention. However, the role NRF2 plays in environmental pollutant-induced toxicity has not been systematically addressed. Here, we characterize NRF2 function in response to various pollutants, such as metals, pesticides and atmospheric quinones. NRF2 related signaling pathways and epigenetic regulations are also reviewed.

Keywords: Air pollutants; Epigenetic modifications; Heavy metals; NRF2; Pesticides; Redox signaling pathways.

Graphical abstract

Fig. 1

Scheme illustration of the activation of redox signaling pathways. Redox signaling pathways are composed of sensor proteins with deprotonated thiol groups (S) and their targeted effector molecules. Under basal condition, the effector molecules are suppressed by the sensor proteins. When electrophiles (E) or reactive oxygen species (ROS) are present, the sensor proteins are inhibited by S-modification, resulting in activation of the effector molecules. This activation of effector molecules such as transcription factors or kinases leads to the activation of redox signaling pathways.

Fig. 2

Structures of a variety of chemicals that serve as ROS generators and modifying agents in the environment. The ROS generators in pink circle are redox active and thus cause redox cycle reaction associated with ROS production. The modifying agents cause covalent binding to nucleophiles such as protein cysteine residues. 1,2-Naphthoquinone and 1,4-naphthoquinone, however, can generate ROS by both redox cycling and direct protein modification.

Fig. 3

Average ambient concentrations of various toxicants in an atmospheric sample at the University of Birmingham. The data is derived from Delgado-Saborit JM et al. [257]. An ambient air sample, taken for 5 days in Birmingham, is analyzed by GC-MS. The black and white bars indicate average ambient concentrations of aromatic hydrocarbons in the particle phase and vapor phase, respectively.

Fig. 4

The generation of quinones and the activation of redox signaling pathway. (A) Polyaromatic hydrocarbons, such as phenanthrene undergoes photo-oxidation in the environment or metabolic activation by enzymes, yielding its quinone. (B) 9,10-Phenanthraquinone (9,10-PQ) is reduced by enzymes such as NAD(P)H quinone dehydrogenase (NQO1) or aldo-keto reductase (AKR) to 9,10-dihydroxyphenanthrene (9,10-PQH₂), which is conjugated with glucuronic acid by glucuronosyltransferases (UGT) and then excreted viamultidrug-associated proteins (MRP). 9,10-PQH₂ is also able to react with superoxide (O₂^•–) to form its semiquinone radical (9,10-PQ^•–) and hydrogen peroxide (H₂O₂). Alternatively, 9,10-PQ^•– is generated by disproportionation reaction of 9,10-PQ with 9,10-PQH₂. The 9,10-PQ^•– produced interacts with molecular oxygen (O₂) to form 9,10-PQ and O₂^•–. Thus, H₂O₂ during these redox cycle reactions of 9,10-PQ could activate redox signaling pathways mimicking endogenous H₂O₂.

Fig. 5

NRF2 signaling pathway in the context of environmental pollutants induced redox toxicity and its regulation. Exposure of environmental toxicants such as atmospheric pollutants, pesticides and heavy metals could cause oxidative stress, including ROS and electrophiles. Besides the well-known PTP1B/EGFR, PTEN/AKT and HSP90/HSF1 pathways, NRF2 can be activated. This NRF2 activation can be induced by the negative regulation of KEAP1 through Cys residues or by the inhibition of KEAP1/NRF2 complex stability via p21, p62 and PKC. Upon the dissociation of KEAP1, NRF2 no longer proceeds to the ubiquitination and degradation, resulting in the translocation to the nucleus. The translocated NRF2 heterodimerizes with other nuclear factors such as sMAF and binds to AREs, driven the activation of detoxing enzymes and antioxidants. This process is also epigenetically regulated. For instance, the hypermethylation of KEAP1 promoter results in NRF2 nuclear translocation, while the hypermethylation of NRF2 promoter represses NRF2. Environmental pollutants could modulate histone acetylation through histone acetyltransferases (HATs) or histone deacetylases (HDACs). Finally, miRNAs and LncRNAs also involve in this regulation process.