Our living environment is populated by numerous structurally heterogeneous chemicals that can have a potentially deleterious impact on health once inside the body. Evidence indicates that highly reactive chemicals, in particular, affect homeostasis by mutually interacting with biological macromolecules. At the same time, there are cellular signal transduction pathways that help to maintain homeostasis by responding appropriately to environmental changes within the organism. It is known that the failure of cellular signaling can lead to cancer, lifestyle-related diseases and autoimmune disorders. Interestingly, oxidative modification of sensor proteins with reactive cysteine residues having a low pKa often plays a role in this signal activation via the signal transduction pathways involved in redox regulation of oxidative stress and other phenomena.
For example, PTEN/Akt signaling and PTP1B/EGFR signaling (involved in cell survival and cell proliferation) enhance anti-apoptotic activity and cell proliferation through activation of the kinases Akt and EGFR in response to oxidative modification of the thiol groups of the sensor proteins PTEN and PTP1B. In Keap1/Nrf2 signaling (involved in responding to oxidative and electrophilic stresses), activation of transcription factor Nrf2 through chemical modification of the thiol groups of the sensor protein Keap1 induces gene expression of antioxidant proteins and phase II xenobiotic metabolizing enzymes. With HSP90/HSF-1 signaling (involved in protein quality control), activation of HSF-1 transcription factor through chemical modification of HSP90 by electrophilic ligands of the type that activate Nrf2 increases expression of HSPs. The research suggests that when thiol groups in sensor proteins are subject to chemical modification, there is a system to activate the stress response molecules that they regulate.
Many environmental electrophiles that covalently bind to thiol groups in proteins to form adducts are present in the atmosphere, water and food. Typical examples of environmental electrophiles are crotonaldehyde and the naphthalene oxidant naphthoquinone, which are found in the environmental pollutant PM2.5 and cigarette smoke; methylmercury, which accumulates in large edible fish due to biological concentration; cadmium in rice; formaldehyde in building materials; acrylamides in potato chips and other foods; and lead that leaches from lead water pipes. Chemical modification of proteins that play an important biological role appears to underlie the toxicity of these chemical substances, but the details are unknown (Figure 1). Hitherto, electrophilic chemicals have been identified as the gbad guysh responsible for carcinogenicity and tissue injury, but the discovery of electrophile response elements (EpRE) within the organism and the endogenous production of electrophiles has focused attention on a ggood guyh role for some of these molecules in response to oxidative stress and inflammation. The hope now is to elucidate the intracellular system that controls the reactivity of electrophiles.
In the current study, we examine two aspects: the activation of signal transduction involved in cell survival, cell proliferation and defense against toxicity when environmental electrophiles trigger chemical modification of sensor proteins as well as the failure of these signaling pathways that results from increased exposure levels (Figure 2). We also show that reactive sulfur species produced in the body regulate inactivation of environmental electrophiles and the associated signal transduction pathways and also defend against toxicity (Figure 2). The research will shed more light on the toxicity mechanism of environmental electrophilic ligands and contribute to mitigation of health risks.