Genotoxicity of Pesticides a Review of Human Biomonitoring Studies Claudia Bolognesi

Introduction of Genotoxic Stress

In genetics, genotoxicity describes the property of chemic agents that impairment the genetic data within a cell causing mutations(Genotoxicity is frequently confused with mutagenicity. All mutagens are genotoxic, whereas not all genotoxic substances are mutagenic.). The amending tin can have direct or indirect furnishings on the Deoxyribonucleic acid: the induction of mutations, mistimed result activation, and direct DNA damage resulting in mutations. Of form, there are exist several of import defense mechanisms to response genotoxic stress. These responses are expected to exist very complex, involving various cellular factors that form an extensive signal transduction network. This network includes a protein kinase cascade that connects the detection of Deoxyribonucleic acid damage to the activation of transcription factors, which in turn regulate the expression of genes implicated in DNA repair, cell wheel arrest and programmed jail cell death (apoptosis). What's worse is heritable changes tin touch either somatic cells of the organism or germ cells to be passed on to future generations. Cells foreclose expression of the genotoxic mutation by either Deoxyribonucleic acid repair or apoptosis, so the impairment may not ever be fixed leading to mutagenesis.

Information technology has long been acknowledged that exposure to sure chemicals is associated with the development of human cancers. For example, this linkage has been made between aflatoxins and liver cancer, amine dyes and bladder cancer, benzene and leukemia, vinyl chloride and hepatic cancer and smoking and lung cancer. To date, many homo carcinogens have been identified, nearly of which are categorized as genotoxic agents, significant that these chemicals target DNA and produce alterations in the genetic material of the host. Such environmental agents are only i source of genotoxic stress, with other sources including UV and ionizing irradiation (IR), therapeutic agents and the products of normal metabolism. As a result, human cells are constantly exposed to a variety of genotoxic stresses. To cope with the resulting damage to cellular DNA, cells have developed a repertoire of responses that ensure the normal growth and survival of the organism. A logical upshot, therefore, is that alterations in these responses may be the basis for carcinogenesis. For this reason, a improve understanding of cellular responses to genotoxic stress is important in the prevention and treatment of human being cancers.

Cellular Genotoxic Responses

Extensive studies from multiple disciplines take explored the mechanisms of the cellular genotoxic responses, leading to the identification of many of the cellular components. The genotoxic stress responses can be envisioned every bit a point transduction pour in which DNA lesions deed equally an initial signal that is detected by sensors and passed down through transducers. Somewhen the effectors receive the signal and execute the various cellular functions. Studies bear witness that a large group of serine-threonine protein kinases, named the mitogen-activated protein kinases (MAPKs), along with their upstream kinases, have been shown to play prominent roles in the cellular genotoxic responses. Three major classes of MAPKs, i.e. extracellular point-regulated kinase (ERK), c-Jun Due north-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 (also known every bit SAPK2, RK, CSBP or Mxi2), tin all exist activated by various genotoxic stresses. The activated MAPKs and so translocate to the nucleus and phosphorylate scores of target proteins, including many transcription factors. Amidst these transcription factors is the tumor suppressor p53 protein, which plays such an important role in the genotoxic stress responses that information technology is called 'universal sensor for genotoxic stresses'.

Although the general moving picture of the MAPK cascade is relatively clear, the actual receptors or sensors for the Deoxyribonucleic acid impairment signal are still elusive. However, information technology is hypothesized that some multiprotein complexes that are involved in DNA maintenance or repair may as well office as Dna damage sensors. For case, certain members of the Rad family, which tin can form protein complexes that function in prison cell checkpoint regulation, could act as potential sensors. Others have suggested that members of the phosphatidylinositol 3-kinase (PI-3) superfamily (include mutated (ATM), ATM- and Rad3-related (ATR), ATX/SMG-ane, mTOR/FRAP and Deoxyribonucleic acid-dependent protein kinase (DNA-PK) in humans.), which are activated at very early stages of the DNA damage response, could serve as the sensors, also every bit initiators, of the ensuing cellular genotoxic stress response. In process of genotoxic stress responses, there have 3 kinases play key roles in human, namely ATM, ATR and DNA-PK. They can induce genotoxic stress responses, such as, DNA repair, cell bicycle arrest and apoptosis. Later on DNA damage is produced, the cells will make two selections. First, Deoxyribonucleic acid is checked for damage by Deoxyribonucleic acid damage checkpoints. Provided that the DNA is damaged, the cell cycle is stopped by triggering a cell cycle arrest response. The advantage of this is the instance that, on the one hand, it tin preclude the damaged Deoxyribonucleic acid from being transferred to the girl cells; on the other hand, it can requite the cells fourth dimension to repair the damage. Second, the cell will determine the extent of genomic impairment. If the genomic damage tin be repaired, the prison cell can still survive; if the prison cell genome impairment is severe, it will lead to apoptosis. The principle of determining the extent of genomic harm in cells is non completely clear. Nevertheless, an explanation was given by studying the tumor suppressor gene P53. The study found that the expression level of P53 changes in accordance with the caste of damage. When the degree of harm is low, low levels of P53 volition mediate cell wheel repression and Dna damage repair; when the degree of DNA damage is high, high levels of P53 volition mediates apoptosis.

Clinical Significance

Genotoxic effects such as deletions, breaks and/or rearrangements can lead to cancer if the damage does not immediately lead to cell death. Dna damage is an important and ubiquitous type of stress that cells are exposed to over the life span of the organism. Sources of DNA-damaging agents, such every bit free radicals and peroxides generated during normal physiologic processes and during inflammation, tin be endogenous, or they can exist exogenous from the myriad of potentially dissentious chemical and concrete agents that nosotros are exposed to in the environment. Since damage always occurs, if the DNA-damaged cells cannot be repaired or apoptotic, its genome is passed on to the offspring. Changes acquired by damage are preserved in the form of mutations in the genome of the cell, somewhen leading to cancer. Because the importance of DNA damage, the organism be able to respond to this type of stress in a manner coordinating to its response to other stresses, such equally rut shock, with induction of a variety of different genes. These responses tin can keep the homeostases and the health of the organism by maintaining the stability of genomic. An improved understanding of these responses is important in the tumorigenesis.

References:

1. Roman Five., Kondratov, Marina P. A., Circadian proteins in the regulation of cell cycle and genotoxic stress responses. Trends in Cell Biology. 2007, 17(vii): 311-317.
2. Jun Y., et al. ATM, ATR and Dna-PK: initiators of the cellular genotoxic stress responses. Carcinogenesis. 2003, 24(10): 1571–1580.
3. Bolognesi, Claudia, Genotoxicity of pesticides: A review of human biomonitoring studies. Mutation Research. 2003, 543: 251–272.

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