Late-onset Increases in Oxidative Stress and Other Tumorigenic Activities and Tumors With a Ha-ras Mutation in the Liver of Adult Male C3H Mice Gestationally Exposed to Arsenic

Nohara, Keiko; Tateishi, Yukiyo; Suzuki, Takehiro; Okamura, Kazunori; Murai, Hikari; Takumi, Shota; Maekawa, Fumihiko; Nishimura, Noriko; Kobori, Masuko; Ito, Takaaki

doi:10.1093/toxsci/kfs203

Cited by 48 publications

(56 citation statements)

References 44 publications

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“…In the last few years, it has been reported that the expression of CRELD2 and MANF are elevated in several physiological conditions, which are not restricted to the central nervous system. 23,[37][38][39] Therefore, further characterization of MANF and CRELD2 inside and outside cells under pathophysiological conditions may give new insights into the onset and progression of ER stress-related diseases. Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Role of MANF in Regulating the Secretion of CRELD2

Oh‐hashi

Norisada

Hirata

et al. 2015

Biological & Pharmaceutical Bulletin

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We recently demonstrated that the secretion of two novel endoplasmic reticulum (ER) stress-inducible proteins, cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) and mesencephalic astrocyte-derived neurotrophic factor (MANF), are oppositely regulated by the overexpression of 78 kDa glucose-regulated protein (GRP78). In the present study, we found that the co-transfection of CRELD2 and MANF remarkably enhanced the secretion of CRELD2 without affecting the expression level of GRP78. To identify the structural features of CRELD2 and MANF involved in this process, we generated several CRELD2 and MANF expression constructs. The deletion of the four C-terminal amino acids, either REDL in CRELD2 or RTDL in MANF, abolished the increased secretion of CRELD2 induced by the co-expression of MANF. The deleted mutation of MANF partially abolished the increased secretion of wild type CRELD2 (wtCRELD2) as a positive action of wild type MANF (wtMANF), even when we added the amino acid sequence RTDL at the C-terminus of each mutated MANF construct. Enhanced green fluorescent protein (EGFP), which was tagged with the signal peptide sequence at the N-terminus and four C-terminal amino acids (KEDL, REDL or RTDL), were retained intracellularly, but they did not enhance the secretion of wtCRELD2. Taken together, our data demonstrate that MANF is a factor in regulating the secretion of CRELD2 through four C-terminal amino acids, RTDL and REDL, and the fluctuation of intracellular MANF seems to potentiate the secretion of CRELD2.Key words endoplasmic reticulum; chaperone; 78 kDa glucose-regulated protein (GRP78); cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2); mesencephalic astrocyte-derived neurotrophic factor (MANF)The folding and modification of newly synthesized transmembrane and secretory proteins in the endoplasmic reticulum (ER) is maintained by a variety of mechanisms.1,2) Under some pathophysiological conditions, certain ER functions become disordered and then unfolded and/or misfolded proteins are accumulated in the ER.3,4) Abnormal protein retention results in ER stress and activation of the three canonical ERresident stress sensors; protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), 5) inositol-requiring enzyme 1 (IRE1) 6) and activating transcription factor 6 (ATF6), 7) induces a variety of genes.8-12) Among them, growth arrest and DNA damage-inducible protein 153 (GADD153) is well-known to promote stress-induced cell death by activating caspases. 8,9) ER resident molecular chaperones such as 78 kDa glucoseregulated protein (GRP78) are reported to alleviate the stress by properly folding and degrading unfolded proteins and attenuating ER stress signals. 10,11) We previously identified the cysteine-rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) gene as a novel ER stress-inducible gene and demonstrate that ATF6 positively regulates the transcription of the CRELD2 gene through a well-conserved ER stress response element (ERSE) in the proximal regio...

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Section: Discussionmentioning

confidence: 99%

Characterization of the Role of MANF in Regulating the Secretion of CRELD2

Oh‐hashi

Norisada

Hirata

et al. 2015

Biological & Pharmaceutical Bulletin

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“…Offspring from the dams received no additional iAs exposure (although some exposure would also occur during lactation, particularly in the first few postnatal days) and were followed through adulthood, at which time they were sacrificed and examined for tumor development. This model was also used in four subsequent studies from the same laboratory (Tokar et al, 2010(Tokar et al, , 2012Waalkes et al, 2006aWaalkes et al, , 2006bWaalkes et al, , 2004 (Waalkes et al, 2006a and2006b report data from the same study for males and females, respectively), as well as in one additional study by Nohara et al (2012). All of the NIEHS studies were conducted at the National Cancer Institute's Frederick, MD animal facility.…”

Section: Mouse Transplacental Carcinogenesis Modelmentioning

confidence: 99%

“…If postnatal iAs exposure is indeed protective for mice, even after in utero exposure to iAs, as data from Ahlborn et al (2009) suggest, it raises questions about the relevance of in utero-only exposure studies since this would be an unlikely exposure pattern for humans. Nohara et al (2012) adapted the NIEHS transplacental carcinogenesis protocol to evaluate potential mechanisms of liver carcinogenesis in C3H mice, which have a high rate of spontaneous liver tumors. Nohara and colleagues administered 0 or 85 ppm sodium arsenite to pregnant dams (n not reported) during GD 8-18.…”

Section: Other Transplacental Carcinogenesis Studiesmentioning

confidence: 99%

“…The Nohara et al (2012) study evaluated only liver tumors and, like the majority of studies from the NIEHS laboratory, reported an increased incidence of liver tumors in male mice, but not in females (although statistics were not provided). In the most direct comparison from another laboratory, Ahlborn et al (2009) reported no increased incidence of any tumor type in the susceptible C3H mouse strain, nor was there evidence of increased hyperplasia or preneoplastic lesions.…”

Section: Concordance Of Tumor Sitesmentioning

confidence: 99%

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In utero arsenic exposure in mice and early life susceptibility to cancer

Garry

Santamaria²,

Williams

et al. 2015

Regulatory Toxicology and Pharmacology

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In its review of the U.S. Environmental Protection Agency's toxicological review of inorganic arsenic (iAs), the National Academy of Sciences identified carcinogenic endpoints among the highest priority health effects of concern and stated the need to consider evidence that early life exposures may increase the risk of adverse health effects. Recent studies in mice suggest that in utero exposure to arsenic increases susceptibility to cancer later in life. These data are striking in light of the general lack of evidence for carcinogenicity in rodents exposed to iAs. To evaluate the transplacental carcinogenic potential of iAs, a detailed analysis of the toxicology literature evaluating the role of in utero arsenic exposure in carcinogenesis was conducted. Bladder, lung, and skin tumors, which are the tumor types most consistently reported in humans exposed to high arsenic levels, were not consistently increased in mouse studies. There was also a lack of concordance across studies for other tumor types not typically reported in humans. Therefore, we considered methodological and other critical issues that may have contributed to variable results and we suggest additional studies to address these issues. It was concluded that the available data do not provide evidence of a causal link between in utero arsenic exposure and cancer or indicate early life-stage susceptibility to arsenic-induced cancer, particularly at environmentally relevant doses.

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“…This process is believed to play a key role in tumorigenesis, as it favours the increase of oxidative stress that can cause DNA damage and, thus, genetic mutations that are commonly expressed as tumour formation (Nohara et al 2012).…”

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confidence: 99%

Influence of trace elements in the epigenetic of mammals

Méndez-Rodríguez¹,

Álvarez-Castañeda²

2014

Therya

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Introduction: Chronic exposure to toxic levels of elements such as arsenic, cadmium, lead, mercury, nickel and others trace elements might cause abnormalities in gene expression affecting metabolic pathways such as those related to trace elements detoxification and the reproductive ability of animals. Rodent species have been the subject of several studies examining the physiological consequences of exposure to toxic levels of arsenic, cadmium and nickel, and how those elements affect their epigenetic mechanisms such as DNA methylation. Results from those studies can be used as an approach of the effects that can potentially occur on small mammals found in sites altered by geochemical or anthropogenic activities (e. g. mining, industrial waste).Methods: An exhaustive literature review was conducted aimed to gain a better understanding of epigenetics, identifying mechanisms involved in the toxicity of trace elements, elucidating the effect of those trace metals in the epigenetics of genes involved in detoxification mechanisms and, finally, determining whether damages caused by exposition to high levels of trace elements are equally evident on any tissue from the same organism.Results and Discussion: Pollutants can influence methylation of DNA patterns, but not all of them follow the same pathway. This varies widely among groups of trace elements or organic compounds. In addition to concentration and time of exposure, a number of other factors affect the toxicity pathway, including age, sex, food sources and, especially, the physiology of the species. Even within the same organism, the methylation patterns associated to a given element vary between tissues. Therefore, selecting the most appropriate tissue for discerning the animal´s actual condition is key when assessing the actual health status of wildlife species. Further studies are needed to better characterize the interactions between DNA methylation and trace elements, and elucidate potential mechanisms or interventions that can help to reduce their effects on wildlife health.Key words: ADN methylation, gene, pollution, trace elements, toxicity.La exposición crónica a niveles tóxicos de elementos como arsénico, cadmio, plomo, mercurio, níquel y otros elementos traza, puede causar alteraciones en la expresión de diversos genes afectando procesos metabólicos como los relacionados con la detoxificación de elementos traza y la capacidad reproductiva de los animales. Las especies de roedores han sido objeto de varios estudios que examinan las consecuencias fisiológicas de la exposición a niveles tóxicos de arsénico, cadmio y níquel y cómo estos elementos afectan sus mecanismos epigenéticos, tales como la metilación del ADN. Los resultados de esos estudios pueden ser utilizados como una aproximación de los efectos que potencialmente pueden ocurrir en pequeños mamíferos que se encuentran en sitios alterados por actividades geoquímicas o antropogénicas (por ejemplo, minería, residuos industriales).Se llevó a cabo una exhaustiva revisión de la literatura con objeto d...

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Late-onset Increases in Oxidative Stress and Other Tumorigenic Activities and Tumors With a Ha-ras Mutation in the Liver of Adult Male C3H Mice Gestationally Exposed to Arsenic

Cited by 48 publications

References 44 publications

Characterization of the Role of MANF in Regulating the Secretion of CRELD2

Characterization of the Role of MANF in Regulating the Secretion of CRELD2

In utero arsenic exposure in mice and early life susceptibility to cancer

Influence of trace elements in the epigenetic of mammals

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