Eventually it was found that these particles were viruses and that their genetic machinery coded for protein kinases, that phosphorylated tyrosine sites on other proteins [ 56 , 57 , 58 , 59 ].
PTKs are a diverse group of trans-membrane enzymes in which the extracellular portion acts as a receptor for ligands such as epidermal growth factor, fibroblast growth factor, insulin and insulin-like growth factors, erythropoietin, etc. Normally monomeric, the binding of a ligand causes dimerization of polypeptide chains that results in phosphorylation on tyrosines of intracellular proteins.
The mechanism linking extracellular ligand formation and intracellular kinase activity is unknown [ 60 , 61 ]. The cytokine receptors do not act as kinases but when stimulated by specific cytokines activate the JAKs which are a group of kinases that constitute the Janus family of kinases. Baker et al. They postulated that JAKs may be associated with the receptors but are inactive until the receptor is bound by a ligand.
At that point dimerization occurs leading to activation of kinase activity by phosphorylation of their tyrosine residues. The activated JAKs may now phosphorylate the receptor to create docking sites for a number of signaling molecules including STATs, other Src kinases, phosphatases, etc.
Once the signal has passed into the cell membrane via either of these mechanisms there are a number of possible pathways by which the signal may reach the nucleus and impact on the DNA. The literature is profusely illustrated with colorful schemes showing the many intracellular signaling pathways that transmit the signals derived from the kinases the activities of which are influenced by trans-membrane transduction through the cell to directly or indirectly influence transcription at the level of DNA.
Rather than review each of the postulated pathways and their impact, it would be instructive to examine the report of a recent study that attempted to examine the roles of several intracellular signaling pathways below the level of membrane signal transduction in bone marrow cells by adding inhibitors of each of several pathways and measuring their effects on the production of colony-forming units in vitro.
Bugarski et al. They recognized that leukemias are usually characterized by the excessive growth of incompletely differentiated bone marrow precursor cells.
The early stages of differentiation involve activation of HSCs leading to a bifurcation whereby one branch proceeds to differentiate along the lymphoid cell line and the other along the myeloid cell lines, i. Their experiment was specifically to measure the impact of inhibition of specific signaling pathways, in mouse bone marrow, on the production of BFU-E, an early erythroid precursor , CFU-E a more highly differentiated erythroid precursor , and CFU-GM a precursor to granulocytes and macrophages.
They asked the following question: If hematopoietic growth factors and cytokines activated by signal transduction at each of their receptors at the same time, thereby turning on a number of signaling cascades, how could this process lead to differentiation of specific precursors?
The experiment that they designed was to determine what the effect would be on either erythroid or myeloid developing cells if they added inhibitors to each of several signaling pathways but allowed the remainder of the signaling pathways to proceed unchecked. They examined the roles of the PTKs, the mitogen-activated protein kinase MAP , and the phosphoinositidekinases PI-3 signaling pathways on each of the three stages of differentiation in the myeloid or erythroid lineages.
The cytokines used in the cultures, i. The strategy used was to add inhibitors, which they considered to be specific for the signaling pathways to cell cultures and to then measure the development of the colony forming units.
SP, which inhibits JNK suppressed all progenitors [ 64 ]. A study of PI-3 inhibitors showed that the selective inhibitor LY, the irreversible inhibitor Wortmannin, and the non-selective inhibitor quercetin suppressed the growth of all progenitors studied. The transcription factor NFkB suppressed all cultures. In , the U.
However, these studies did not attempt to explore the effects of the metabolites on signaling mechanisms. The studies described by Bugarski et al. They make it clear that these are complex interactions and the results may reflect on more than a single signaling pathway. Furthermore, the inhibitors may impact on different stages of differentiation in more than a single lineage.
The impact of the inhibitors may occur via an effect on receptors, enzymes, microenvironmental factors, etc. However, the use of a similar strategy to study the effects of benzene, that are largely the result of the generation of a variety of metabolites, provides an opportunity to propose any of several different challengeable hypotheses to evaluate a number of different potential mechanisms which could lead to hematotoxicity or leukemogenesis.
A key feature of organs throughout the body is their accessible morphology that can be observed grossly, microscopically and even at a level beyond the capability of the eye if one uses an electron microscope. These techniques are possible because the organs can be viewed in situ or can be removed without loss of their structural characteristics even after dissection. HSCs arise in the bone marrow and were long thought be a homogeneous population of cells.
Observation of the bone marrow has been limited because removal from the bone results in loss of any structural features that it may contain. Recent studies of bone marrow function in vivo and in vitro have led to the conclusion that bone marrow may be a highly structured organ. Wilson and Trumpp [ 5 ] and Butler et al. One type may be a storage site for quiescent HSCs that are maintained in G 0 and may undergo classical symmetrical mitosis, i.
Another may be a niche in which HSCs undergo asymmetric mitosis, i. Muller-Sieburg et al. The lymphoid type predominates early in life, and the myeloid type increases with age. Dykstra and de Haan discussed changes in HSCs that occur through aging [ 68 ]. As a result, we have age-related abatement of regenerative potential, reduced immune-competence, and the greater likelihood of myelogenous diseases such as myelodysplastic syndrome and leukemia.
Rossi et al. The cells demonstrate impaired renewal and proliferative potential, increased apoptosis, and accumulation of DNA damage. Detection of DNA damage and the response are controlled by a signal transduction pathway that may result in DNA repair, alteration of the cell cycle or apoptosis.
Critical to the fidelity of these responses are checkpoints that help to direct the response. Wang et al. The authors noted that HSCs enter the cell cycle only once every 3—4 months [ 71 ].
Aberrant DNA repair can occur in quiescent stem cells despite cell cycle arrest [ 72 ]. Quiescent cells are resistant to apoptosis stimulated by DNA damage and more likely to survive despite DNA damage [ 73 ]. Thus, differentiation may eliminate accumulation of genotoxic damage in quiescent HSCs and protect against subsequent development of DNA-associated damage leading to cancer.
Whether or not cancers arise from stem cells has been a matter of some debate [ 74 , 75 ]. Prevailing theories of carcinogenesis suggest that attack on DNA by a reactive metabolite s of a chemical, or by reactive oxygen generated during the metabolism of the chemical, results in either covalent binding of the metabolite s to DNA or oxidative damage caused by reactive oxygen species.
Failure to repair DNA from such attacks may cause carcinogenic mutations and the generation of cells that can give rise to various forms of cancer. One can argue that if these cells undergo self-renewal, and if their progeny can differentiate albeit in limited fashion and proliferate, they might be termed cancer stem cells. The concept of the cancer stem cell provides a useful basis for this discussion.
These cells displayed the capacity to differentiate and proliferate, as well as to self-renew. Chemical carcinogenesis appears to provide a satisfactory explanation of tumors induced by many chemicals such as aflatoxin [ 77 ], benzo[a]pyrene [ 78 ], and others where high levels of DNA adduct formation are observed.
In the case of benzene, and its role in leukemogenesis, DNA adducts have been described [ 79 ] but little DNA binding has been observed in vivo in animal test species [ 80 ]. Alternatively, it has been suggested that the benzene metabolite 1,4-benzoquinone may inhibit topoisomerase II and, thereby, inhibit the annealing of strand breaks in DNA resulting in mutations [ 81 , 82 , 83 ].
The use of topoisomerase II inhibitors as cancer chemotherapeutic agents often results in leukemia following remission of the earlier tumor. Topoisomerase II inhibition may play a role in the induction of benzene-induced leukemia. Another relatively unexplored potential impact of benzene metabolites that may impact on leukemogenesis is extensive covalent binding to proteins [ 84 ].
The many signaling pathways described above may be subject to attack by reactive metabolites of benzene leading to inactivation of critical signaling proteins or their receptors. The discussion by Wilson and Trumpp and their description of how niches may function in hematopoiesis plus the discussion of HSCs above suggests possible mechanisms which may be involved in the generation of benzene-induced leukemias [ 5 ].
One may visualize normal hematopoiesis involving two types of niches. In one Type A HSCs undergo asymmetric mitosis as needed generating a HSC and a cell poised to enter the differentiation scheme leading to mature circulating blood cells.
Upon recruitment their numbers may be restored via self-renewal by symmetric mitosis. From time to time trauma, disease or DNA damage via reactive metabolites of environmental chemicals or reactive oxygen species produced during their metabolism could lead to cell death and a reduction in the functional residual capacity of the Type A niche to replace lost cells. It should be noted that exposure to benzene is likely to lead to bone marrow cell death and DNA damage at any stage of life.
Chronic exposure would exacerbate these effects. Indeed people chronically exposed to benzene demonstrate chromosome aberrations prior to developing leukemia. HSCQs could then undergo self-renewal to maintain the proper number of stored cells. It is noteworthy that there are reports suggesting that the time from initial exposure to benzene and subsequent development of leukemia may be anywhere from 5 to 20 years. Over time reduced capacity of mechanisms such as DNA repair, apoptosis, or effective checkpoints, or other genetic differences may have determined the time needed for leukemogenesis.
The aim of this discussion has been to reprise some aspects of the interaction between benzene and the people whose lives it may impact. The review is somewhat incomplete because time and space do not permit a more exhaustive presentation the literature on benzene. However, there has been an attempt to suggest that there are some areas that require further evaluation. Direct effects of reactive metabolites, e. The factors involved in conversion of a normal cell to a leukemia cell, that may be termed a leukemia stem cell, should be examined.
Several studies aimed at identifying cancer stem cells may provide a starting point for examining benzene-associated leukemia stem cells. Recent findings describing the bone marrow as a series of niches each of which plays a role in hematopoiesis are just beginning to be understood in terms of normal bone marrow function and must be evaluated with respect to the effects of hematotoxic agents.
The study of the mechanism of benzene toxicity and leukemogenesis has progressed slowly with about a half century intervening between descriptive initial studies of Santesson, Selling and Weiskotten and the early studies of Parke and Williams directed to understanding the mechanisms involved.
Since then we have extended our appreciation of benzene metabolism. The next steps require that we take advantage of developments in studies of the bone marrow niches, stem cell biology, and the effects of perturbation of cell signaling if we are to delineate the mechanisms by which benzene causes leukemia.
The author would like to thank the colleagues who have reviewed this manuscript and have made significant suggestions for its improvement. National Center for Biotechnology Information , U. Published online Aug Robert Snyder. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Excessive exposure to benzene has been known for more than a century to damage the bone marrow resulting in decreases in the numbers of circulating blood cells, and ultimately, aplastic anemia.
Keywords: benzene, bone marrow, niche, leukemia, benzene metabolism, stem cells, cell signaling, signal transduction, cytokines, cancer stem cells. Introduction Benzene, the commercial use of which dates to the late nineteenth century, was one of the earliest industrial chemicals demonstrated to affect the health of large numbers of workers [ 1 , 2 ].
Current Scientific Issues in the Study of Benzene Leukemogenesis Mechanistic toxicologists are of the opinion that we can make more rapid progress toward understanding the relationship between benzene exposure and benzene-induced leukemia if we can decipher the biochemical mechanisms that impel leukemogenesis [ 3 ].
Benzene Production To understand the magnitude of the benzene problem in the modern world it would be useful to present a brief summary of how benzene production has grown since its discovery. Protection against Benzene Exposure The approach used in many nations to protect workers from excessive exposure to chemicals has been to explore the dose-response relationship linking airborne concentrations of the chemical to adverse responses. Background Occupational Medicine and Toxicology are two closely interrelated disciplines.
Leukemia Throughout history physicians, when confronted with a diseased patient, have attempted to identify the disease based on examination of the patient and references to the medical literature. Benzene Exposure and Leukemia The suggestion that benzene exposure could result in leukemia was more difficult to establish than the demonstration that benzene could induce aplastic anemia.
Benzene Metabolism Xenobiotic metabolism usually modifies chemicals to make them more water-soluble by introducing oxygen or other polar groups into the potentially dangerous chemical. Figure 1. Open in a separate window. Regulation of Hematopoiesis The regulation of the hematopoietic process is primarily maintained by a series of cytokines plus other proteins via processes termed signaling. Intracellular Signaling The literature is profusely illustrated with colorful schemes showing the many intracellular signaling pathways that transmit the signals derived from the kinases the activities of which are influenced by trans-membrane transduction through the cell to directly or indirectly influence transcription at the level of DNA.
Hematopoietic Stem Cells HSCs A key feature of organs throughout the body is their accessible morphology that can be observed grossly, microscopically and even at a level beyond the capability of the eye if one uses an electron microscope. Cancer Stem Cells Whether or not cancers arise from stem cells has been a matter of some debate [ 74 , 75 ].
Conclusions and Future Directions The aim of this discussion has been to reprise some aspects of the interaction between benzene and the people whose lives it may impact. Acknowledgments The author would like to thank the colleagues who have reviewed this manuscript and have made significant suggestions for its improvement.
Conflict of Interest The authors declare no financial or commercial conflict of interest. References 1. Snyder R.
Current concepts of chronic benzene toxicity. CRC Crit. Hunter D. The Diseases of Occupations. Little Brown and Co. The toxicology of benzene. Health Perspect. Santesson C. Wilson A. Bone-marrow haematopoietic-stem-cell niches. Burness M. The stem cell niche in health and malignancy. Cancer Biol. Metcalf D. Hematopoetic cytokines. Newell L. World Bank Group. Hofmann A. Ueber eine sichere reaction auf benzol on a reliable test for benzene Liebigs Ann. Riegel E. Batchelder H.
Chemicals from coal. Production of major commodity chemicals. Ramazzini B. Diseases of Workers. Uglow J. Selling L. A preliminary report of some cases of purpura haemorrhagica due to benzol poisoning. John Hopkins Hosp. Benzol as a leucotoxin. What benzene is Benzene is a chemical that is a colorless or light yellow liquid at room temperature. It has a sweet odor and is highly flammable.
Benzene evaporates into the air very quickly. Its vapor is heavier than air and may sink into low-lying areas. Benzene dissolves only slightly in water and will float on top of water. Where benzene is found and how it is used Benzene is formed from both natural processes and human activities. Natural sources of benzene include volcanoes and forest fires.
Benzene is also a natural part of crude oil, gasoline, and cigarette smoke. Benzene is widely used in the United States. It ranks in the top 20 chemicals for production volume. Some industries use benzene to make other chemicals that are used to make plastics, resins, and nylon and synthetic fibers. Benzene is also used to make some types of lubricants, rubbers, dyes, detergents, drugs, and pesticides. How you could be exposed to benzene Outdoor air contains low levels of benzene from tobacco smoke, gas stations, motor vehicle exhaust, and industrial emissions.
Indoor air generally contains levels of benzene higher than those in outdoor air. The benzene in indoor air comes from products that contain benzene such as glues, paints, furniture wax, and detergents. The air around hazardous waste sites or gas stations can contain higher levels of benzene than in other areas.
Benzene leaks from underground storage tanks or from hazardous waste sites containing benzene can contaminate well water. People working in industries that make or use benzene may be exposed to the highest levels of it. A major source of benzene exposure is tobacco smoke. How benzene works Benzene works by causing cells not to work correctly.
For example, it can cause bone marrow not to produce enough red blood cells, which can lead to anemia. Also, it can damage the immune system by changing blood levels of antibodies and causing the loss of white blood cells. The seriousness of poisoning caused by benzene depends on the amount, route, and length of time of exposure, as well as the age and preexisting medical condition of the exposed person. Immediate signs and symptoms of exposure to benzene People who breathe in high levels of benzene may develop the following signs and symptoms within minutes to several hours: Drowsiness Dizziness Rapid or irregular heartbeat Headaches Tremors Confusion Unconsciousness Death at very high levels Eating foods or drinking beverages containing high levels of benzene can cause the following symptoms within minutes to several hours: Vomiting Irritation of the stomach Dizziness Sleepiness Convulsions Rapid or irregular heartbeat Death at very high levels If a person vomits because of swallowing foods or beverages containing benzene, the vomit could be sucked into the lungs and cause breathing problems and coughing.
Direct exposure of the eyes, skin, or lungs to benzene can cause tissue injury and irritation. Showing these signs and symptoms does not necessarily mean that a person has been exposed to benzene. Global Cancer Research. Cancer Research Infrastructure. Clinical Trials. Frederick National Laboratory for Cancer Research.
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