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Hormesis and Transhormesis in Toxicology and Risk Assessment

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 October 2016) | Viewed by 41904

Special Issue Editors

Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Health Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
Interests: pharmacology; nutrition; toxicology; pharmacy; medical and pharmaceutical chemistry; drug development; drug metabolism; drug safety; pharmacotherapy; food supplements; reactive oxygen species; free radicals; antioxidants; oxidative stress; redox modulation; flavonoids; thiols; glutathione; reactive intermediates; lipid peroxidation; kinetics; structure activity relationship; biomarkers; regulatory issues; food safety
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Health Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
Interests: molecular biology; cell biology; biochemistry; analytical chemistry; pharmacy; medical chemistry; clinical pharmacology; toxicology; reactive oxygen species; free radicals; antioxidants; oxidative stress; redox modulation; nutrition; flavonoids; thiols; glutathione; reactive intermediates; lipid peroxidation; kinetics; structure activity relationship; biomarkers
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Health Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
Interests: pharmacology; nutrition; toxicology; molecular biology; cell biology; reactive oxygen species; free radicals; antioxidants; oxidative stress; redox modulation; flavonoids; thiols; glutathione; reactive intermediates; kinetics; structure activity relationship

Special Issue Information

Dear Colleagues,

To prevent the toxicity of chemicals, ideally we should minimize our exposure. The best case scenario, of course, is to have no exposure at all, but, in the real world, this is not possible. Are we then just ‘sitting ducks’ for toxic chemicals in the environment to damage our bodies at will? No, we are much better prepared than we thought. Living organisms appear to be more flexible than we imagined and our cells have the ability to adapt to the presence of a poison. Perhaps, a little bit of bad might be good for you. This can be exemplified with the poison acrolein, a model compound used in the toxicological research of organ damage, especially that of the lung. Acrolein is present in the environment mainly through its use in the chemical industry and the incomplete combustion of fuel. Moreover, acrolein is a component of cigarette smoke.

Lung cells exposed to a low dose of acrolein are not damaged. On the contrary, the cells adapt and their protection against the poison is upgraded (Sthijns et al. 2014, Adaptation to acrolein through upregulating the protection by glutathione in human bronchial epithelial cells: The materialization of the hormesis concept). In toxicology, the notion that cells are flexible and can adapt has already existed for quite some time. This phenomenon is known as “hormesis”. It appeared that acrolein activates a sensor within the cell prompting the production of more natural antioxidant. In this way, the cells become resistant to doses that were clearly toxic before this adaptation process happened. The results obtained with acrolein demonstrate that this theoretical concept works in practice.

The pitfall is that hormesis should not be misinterpreted as carte blanche to take your daily dose of a poison to improve health; this would be unwise. The challenge is to somehow encourage hormetic adaptation to a toxic compound by another compound. The process that exposure to one compound results in hormetic adaptation to another compound we coin as transhormesis.

A wealth of data underpins the dynamics of cellular protection towards toxic compounds although this cellular flexibility has not yet been acknowledged in risk assessment procedures. Nevertheless, hormesis and transhormesis do influence how toxic a poison might be to us. Indeed, although the cells in our bodies must be ready to protect us at all times it makes no sense to wear a “suit of armour” 24 hours a day when there is no imminent threat. However, the research highlights how our body “senses” chemical threats so that we raise our defensive “shields” in time to protect us. Thus, in this way, our cells become stronger by exposure to a “little bit of bad”.

Prof. Dr. Aalt Bast
Dr. Guido R.M.M. Haenen
Guest Editors

Ms. Mireille M.J.P.E. Sthijns
Co-Guest Editor

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Keywords

  • Hormesis
  • Transhormesis
  • Toxicology
  • Risk assessment
  • Adaptation
  • Exposure

Published Papers (6 papers)

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4130 KiB  
Article
Follicle Loss and Apoptosis in Cyclophosphamide-Treated Mice: What’s the Matter?
by Xiu-Ying Chen, He-Xia Xia, Hai-Yun Guan, Bin Li and Wei Zhang
Int. J. Mol. Sci. 2016, 17(6), 836; https://doi.org/10.3390/ijms17060836 - 30 May 2016
Cited by 76 | Viewed by 6655
Abstract
With increasing numbers of young female cancer survivors following chemotherapy, chemotherapy-induced fertility loss must be considered. Menstrual disorder and infertility are of particular concern in female cancer patients. We showed that treatment with the alkylating agent cyclophosphamide (CTX) could cause severe primordial follicle [...] Read more.
With increasing numbers of young female cancer survivors following chemotherapy, chemotherapy-induced fertility loss must be considered. Menstrual disorder and infertility are of particular concern in female cancer patients. We showed that treatment with the alkylating agent cyclophosphamide (CTX) could cause severe primordial follicle loss and growing follicle apoptosis, resulting in loss of ovarian reserve. SPF C57BL/6 female mice were treated with a single dose of 120 mg/kg of CTX or saline as a control, and both sides of ovaries were collected three or seven days after injection. Following CTX treatment, the ovaries were mostly composed of collapsed oocytes and presented marked cortical fibrosis and a reduced number of follicles, especially primordial follicles. The loss of primordial follicles was confirmed by primordial follicle counting, immunohistochemistry and Western blot detection of DDx4/MVH. Follicle apoptosis was tested by a TUNEL assay and the number of TUNEL-positive follicle cells increased, as expected, in CTX-treated mice. Furthermore, expression of APAF-1 and cleaved caspase-3 was also increased after CTX treatment. Analysis of the PI3K/Akt/mTOR signaling pathway showed that CTX increased phosphorylation of Akt, mTOR and downstream proteins without affecting total levels. These results demonstrated that the CTX treatment led to the hyperactivation of the PI3K/Akt/mTOR signaling pathway in ovaries which may be related to primordial follicle loss and growing follicle apoptosis. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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Review

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712 KiB  
Review
Hormesis and Defense of Infectious Disease
by Sebastian Weis, Ignacio Rubio, Kristin Ludwig, Cynthia Weigel and Elisa Jentho
Int. J. Mol. Sci. 2017, 18(6), 1273; https://doi.org/10.3390/ijms18061273 - 15 Jun 2017
Cited by 22 | Viewed by 5760
Abstract
Infectious diseases are a global health burden and remain associated with high social and economic impact. Treatment of affected patients largely relies on antimicrobial agents that act by directly targeting microbial replication. Despite the utility of host specific therapies having been assessed in [...] Read more.
Infectious diseases are a global health burden and remain associated with high social and economic impact. Treatment of affected patients largely relies on antimicrobial agents that act by directly targeting microbial replication. Despite the utility of host specific therapies having been assessed in previous clinical trials, such as targeting the immune response via modulating the cytokine release in sepsis, results have largely been frustrating and did not lead to the introduction of new therapeutic tools. In this article, we will discuss current evidence arguing that, by applying the concept of hormesis, already approved pharmacological agents could be used therapeutically to increase survival of patients with infectious disease via improving disease tolerance, a defense mechanism that decreases the extent of infection-associated tissue damage without directly targeting pathogenic microorganisms. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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410 KiB  
Review
Hormetic Response to Low-Dose Radiation: Focus on the Immune System and Its Clinical Implications
by Jiuwei Cui, Guozi Yang, Zhenyu Pan, Yuguang Zhao, Xinyue Liang, Wei Li and Lu Cai
Int. J. Mol. Sci. 2017, 18(2), 280; https://doi.org/10.3390/ijms18020280 - 27 Jan 2017
Cited by 67 | Viewed by 9191
Abstract
The interrelationship between ionizing radiation and the immune system is complex, multifactorial, and dependent on radiation dose/quality and immune cell type. High-dose radiation usually results in immune suppression. On the contrary, low-dose radiation (LDR) modulates a variety of immune responses that have exhibited [...] Read more.
The interrelationship between ionizing radiation and the immune system is complex, multifactorial, and dependent on radiation dose/quality and immune cell type. High-dose radiation usually results in immune suppression. On the contrary, low-dose radiation (LDR) modulates a variety of immune responses that have exhibited the properties of immune hormesis. Although the underlying molecular mechanism is not fully understood yet, LDR has been used clinically for the treatment of autoimmune diseases and malignant tumors. These advancements in preclinical and clinical studies suggest that LDR-mediated immune modulation is a well-orchestrated phenomenon with clinical potential. We summarize recent developments in the understanding of LDR-mediated immune modulation, with an emphasis on its potential clinical applications. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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2397 KiB  
Review
PERM Hypothesis: The Fundamental Machinery Able to Elucidate the Role of Xenobiotics and Hormesis in Cell Survival and Homeostasis
by Salvatore Chirumbolo and Geir Bjørklund
Int. J. Mol. Sci. 2017, 18(1), 165; https://doi.org/10.3390/ijms18010165 - 15 Jan 2017
Cited by 39 | Viewed by 5924
Abstract
In this article the Proteasome, Endoplasmic Reticulum and Mitochondria (PERM) hypothesis is discussed. The complex machinery made by three homeostatic mechanisms involving the proteasome (P), endoplasmic reticulum (ER) and mitochondria (M) is addressed in order to elucidate the beneficial role of many xenobiotics, [...] Read more.
In this article the Proteasome, Endoplasmic Reticulum and Mitochondria (PERM) hypothesis is discussed. The complex machinery made by three homeostatic mechanisms involving the proteasome (P), endoplasmic reticulum (ER) and mitochondria (M) is addressed in order to elucidate the beneficial role of many xenobiotics, either trace metals or phytochemicals, which are spread in the human environment and in dietary habits, exerting their actions on the mechanisms underlying cell survival (apoptosis, cell cycle regulation, DNA repair and turnover, autophagy) and stress response. The “PERM hypothesis” suggests that xenobiotics can modulate this central signaling and the regulatory engine made fundamentally by the ER, mitochondria and proteasome, together with other ancillary components such as peroxisomes, by acting on the energetic balance, redox system and macromolecule turnover. In this context, reactive species and stressors are fundamentally signalling molecules that could act as negative-modulating signals if PERM-mediated control is offline, impaired or dysregulated, as occurs in metabolic syndrome, degenerative disorders, chronic inflammation and cancer. Calcium is an important oscillatory input of this regulation and, in this hypothesis, it might play a role in maintaining the correct rhythm of this PERM modulation, probably chaotic in its nature, and guiding cells to a more drastic decision, such as apoptosis. The commonest effort sustained by cells is to maintain their survival balance and the proterome has the fundamental task of supporting this mechanism. Mild stress is probably the main stimulus in this sense. Hormesis is therefore re-interpreted in the light of this hypothetical model and that experimental evidence arising from flavonoid and hormesis reasearch. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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954 KiB  
Review
The Emergence of the Dose–Response Concept in Biology and Medicine
by Edward J. Calabrese
Int. J. Mol. Sci. 2016, 17(12), 2034; https://doi.org/10.3390/ijms17122034 - 05 Dec 2016
Cited by 57 | Viewed by 6384
Abstract
A historical assessment of the origin of the dose–response in modern toxicology and its integration as a central concept in biology and medicine is presented. This article provides an overview of how the threshold, linear and biphasic (i.e., hormetic) dose–response models emerged in [...] Read more.
A historical assessment of the origin of the dose–response in modern toxicology and its integration as a central concept in biology and medicine is presented. This article provides an overview of how the threshold, linear and biphasic (i.e., hormetic) dose–response models emerged in the late 19th and early 20th centuries and competed for acceptance and dominance. Particular attention is directed to the hormetic model for which a general description and evaluation is provided, including its historical basis, and how it was marginalized by the medical and pharmacology communities in the early decades of the 20th century. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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1809 KiB  
Review
Time in Redox Adaptation Processes: From Evolution to Hormesis
by Mireille M. J. P. E. Sthijns, Antje R. Weseler, Aalt Bast and Guido R. M. M. Haenen
Int. J. Mol. Sci. 2016, 17(10), 1649; https://doi.org/10.3390/ijms17101649 - 29 Sep 2016
Cited by 55 | Viewed by 6797
Abstract
Life on Earth has to adapt to the ever changing environment. For example, due to introduction of oxygen in the atmosphere, an antioxidant network evolved to cope with the exposure to oxygen. The adaptive mechanisms of the antioxidant network, specifically the glutathione (GSH) [...] Read more.
Life on Earth has to adapt to the ever changing environment. For example, due to introduction of oxygen in the atmosphere, an antioxidant network evolved to cope with the exposure to oxygen. The adaptive mechanisms of the antioxidant network, specifically the glutathione (GSH) system, are reviewed with a special focus on the time. The quickest adaptive response to oxidative stress is direct enzyme modification, increasing the GSH levels or activating the GSH-dependent protective enzymes. After several hours, a hormetic response is seen at the transcriptional level by up-regulating Nrf2-mediated expression of enzymes involved in GSH synthesis. In the long run, adaptations occur at the epigenetic and genomic level; for example, the ability to synthesize GSH by phototrophic bacteria. Apparently, in an adaptive hormetic response not only the dose or the compound, but also time, should be considered. This is essential for targeted interventions aimed to prevent diseases by successfully coping with changes in the environment e.g., oxidative stress. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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