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[This corrects the article DOI: 10.1371/journal.pone.0130940.].
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Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested.
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Carcinogênese/induzido quimicamente , Carcinogênese/metabolismo , Carcinógenos Ambientais/efeitos adversos , Exposição Ambiental/efeitos adversos , Neoplasias/induzido quimicamente , Neoplasias/metabolismo , Animais , Humanos , Neoplasias/etiologiaRESUMO
Mitochondrial dysfunction has been linked to myriad human diseases and toxicant exposures, highlighting the need for assays capable of rapidly assessing mitochondrial health in vivo. Here, using the Seahorse XFe24 Analyzer and the pharmacological inhibitors dicyclohexylcarbodiimide and oligomycin (ATP-synthase inhibitors), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (mitochondrial uncoupler) and sodium azide (cytochrome c oxidase inhibitor), we measured the fundamental parameters of mitochondrial respiratory chain function: basal oxygen consumption, ATP-linked respiration, maximal respiratory capacity, spare respiratory capacity and proton leak in the model organism Caenhorhabditis elegans. Since mutations in mitochondrial homeostasis genes cause mitochondrial dysfunction and have been linked to human disease, we measured mitochondrial respiratory function in mitochondrial fission (drp-1)-, fusion (fzo-1)-, mitophagy (pdr-1, pink-1)-, and electron transport chain complex III (isp-1)-deficient C. elegans. All showed altered function, but the nature of the alterations varied between the tested strains. We report increased basal oxygen consumption in drp-1; reduced maximal respiration in drp-1, fzo-1, and isp-1; reduced spare respiratory capacity in drp-1 and fzo-1; reduced proton leak in fzo-1 and isp-1; and increased proton leak in pink-1 nematodes. As mitochondrial morphology can play a role in mitochondrial energetics, we also quantified the mitochondrial aspect ratio for each mutant strain using a novel method, and for the first time report increased aspect ratios in pdr-1- and pink-1-deficient nematodes.
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Caenorhabditis elegans/metabolismo , Transporte de Elétrons , Mitocôndrias/ultraestrutura , 2,4-Dinitrofenol/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Carbonil Cianeto p-Trifluormetoxifenil Hidrazona/farmacologia , Dicicloexilcarbodi-Imida/farmacologia , Dinaminas/deficiência , Dinaminas/genética , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Complexo III da Cadeia de Transporte de Elétrons/genética , GTP Fosfo-Hidrolases/deficiência , GTP Fosfo-Hidrolases/genética , Homeostase , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/ultraestrutura , Oligomicinas/farmacologia , Consumo de Oxigênio , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Azida Sódica/farmacologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genéticaRESUMO
In recent decades, there has been a significant expansion in our understanding of the role of astrocytes in neuroprotection, including spatial buffering of extracellular ions, secretion of metabolic coenzymes, and synaptic regulation. Astrocytic neuroprotective functions require energy, and therefore require a network of functional mitochondria. Disturbances to astrocytic mitochondrial homeostasis and their ability to produce ATP can negatively impact neural function. Perturbations in astrocyte mitochondrial function may accrue as the result of physiological aging processes or as a consequence of neurotoxicant exposure. Hydrophobic environmental neurotoxicants, such as 1,3-dinitrobenzene and α-chlorohydrin, cause regionally specific spongiform lesions mimicking energy deprivation syndromes. Astrocyte involvement includes mitochondrial damage that either precedes or is accompanied by neuronal damage. Similarly, environmental neurotoxicants that are implicated in the etiology of age-related neurodegenerative conditions cause regionally specific damage in the brain. Based on the regioselective nature of age-related neurodegenerative lesions, chemically induced models of regioselective lesions targeting astrocyte mitochondria can provide insight into age-related susceptibilities in astrocyte mitochondria. Most of the available research to date focuses on neuronal damage in cases of age-related neurodegeneration; however, there is a body of evidence that supports a central mechanistic role for astrocyte mitochondria in the expression of neural injury. Regional susceptibility to neuronal damage induced by aging by exposure to neurotoxicants may be a reflection of highly variable regional energy requirements. This review identifies region-specific vulnerabilities in astrocyte mitochondria in examples of exposure to neurotoxicants and in age-related neurodegeneration.
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Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Mitocôndrias/efeitos dos fármacos , Degeneração Neural , Síndromes Neurotóxicas/etiologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/fisiopatologia , Medição de Risco , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Nervo Vestibulococlear/efeitos dos fármacos , Nervo Vestibulococlear/metabolismo , Nervo Vestibulococlear/patologiaRESUMO
Regions of the brain with high energy requirements are especially sensitive to perturbations in mitochondrial function. Hence, neurotoxicant exposures that target mitochondria in regions of high energy demand have the potential to accelerate mitochondrial damage inherently occurring during the aging process. 1,3-Dinitrobenzene (DNB) is a model neurotoxicant that selectively targets mitochondria in brainstem nuclei innervated by the eighth cranial nerve. This study investigates the role of age in the regional susceptibility of brain mitochondria-related proteins (MRPs) to oxidation following exposure to DNB. Male F344 rats (1 month old [young], 3 months old [adult], 18 months old [aged]) were exposed to 10 mg/kg DNB prior to mitochondrial isolation and histopathology experiments. Using a high-throughput proteomic approach, 3 important region- and age-related increases in DNB-induced MRP oxidation were determined: (1) brainstem mitochondria are ×3 more sensitive to DNB-induced oxidation than cortical mitochondria; (2) oxidation of brainstem MRPs is significantly higher than in cortical counterparts; and (3) MRPs from the brainstems of older rats are significantly more oxidized than those from young or adult rats. Furthermore, lower levels of DNB cause signs of intoxication (ataxia, chromodacryorrhea) and vacuolation of the susceptible neuropil in aged animals, while neither is observed in DNB-exposed young rats. Additionally, methemoglobin levels increase significantly in DNB-exposed adult and aged animals, but not young DNB-exposed animals. This suggests that oxidation of key MRPs observed in brainstem of aged animals is necessary for DNB-induced signs of intoxication and lesion formation. These results provide compelling evidence that environmental chemicals such as DNB may aid in the acceleration of injury to specific brain regions by inducing oxidation of sensitive mitochondrial proteins.