Induction of Lung Lesions in Female Rats Following Chronic Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Tritscher, Angelika; Mahler, Joel F.; Portier, Christopher J.; Lucier, George W.; Walker, Nigel J.

doi:10.1177/019262330002800601

Cited by 22 publications

(16 citation statements)

References 29 publications

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“…Consistent with this concept, our previous report demonstrated a potential mechanism by which TCDD may act as a lung tumor promoter in an in vivo animal model [15]. In addition, study that used DEN as an initiator and TCDD as a promoter also showed that continuous TCDD exposure is required to promote lung tumorigenesis [1]. Thus, the tumor-promoting effect of TCDD could be the cause of its carcinogenicity, suggesting that TCDD acts as a co-carcinogen.…”

Section: Discussionsupporting

confidence: 53%

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TCDD Promotes Lung Tumors via Attenuation of Apoptosis through Activation of the Akt and ERK1/2 Signaling Pathways

et al. 2014

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a multiple-site, multiple-species carcinogen that induces cancer in multiple organs. The molecular mechanisms underlying TCDD-induced lung tumorigenesis remain unclear. In the present study, a two-stage lung tumorigenesis model was established by administrating a single low dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) combined with TCDD to female A/J mice. The results indicated that TCDD combined with low-dose NNK has a significant tumor-promoting effect compared with TCDD or low-dose NNK alone. Resistance to apoptosis is a hallmark of cancer and is thought to be one of the tumor-promoting mechanisms regulated by TCDD. We performed an additional series of experiments in the normal human bronchial epithelial cell line Beas2B cells, in which TCDD was combined with the apoptosis inducer staurosporine. Our in vitro results confirmed that TCDD could rescue cells from apoptosis induced by staurosporine. The inhibition of apoptosis is likely mediated by the activation of the Akt and ERK1/2 pathways, as determined by the effectiveness of pathway-specific inhibitors in abrogating the anti-apoptotic activity of TCDD. In conclusion, we demonstrated that TCDD promoted NNK-induced lung tumorigenesis and revealed that TCDD inhibits staurosporine-induced apoptosis, at least in part, through the Akt and ERK1/2 signaling pathways.

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Section: Discussionsupporting

confidence: 53%

“…These compounds are formed as industrial by-products [1] and are found as persistent contaminants in the environment, food, human tissues, and human milk [2]. Human exposure to dioxins occurs mainly through contaminated food such as cow's milk, milk products, bovine adipose tissue, hen's eggs and fish [3].…”

Section: Introductionmentioning

confidence: 99%

TCDD Promotes Lung Tumors via Attenuation of Apoptosis through Activation of the Akt and ERK1/2 Signaling Pathways

et al. 2014

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“…The stimulus for this lesion may be damage to the preexisting epithelium due to exposure to ROS or a direct stimulation of the cells that produce certain enzymes. Clara cells are rich in catabolic enzymes, especially those of the pulmonary cytochrome P450 family (Cheville, 1994;Tritscher et al, 2000). CYP1A1 is induced by dioxins and its levels were increased in lung samples from treated animals in this study (data not shown).…”

Section: Immunohistochemical Staining For Gstpimentioning

confidence: 56%

Characterization of Bronchiolar Metaplasia of the Alveolar Epithelium in Female Sprague—Dawley Rats Exposed to 3,3',4,4',5-Pentachlorobiphenyl (PCB126)

et al. 2004

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To test the dioxin toxic equivalency factor methodology, the National Toxicology Program conducted a series of 2-year rat bioassays of dioxin-like compounds. Following gavage exposure of female Harlan Sprague-Dawley rats to 2,3 ,4,4 ,5-pentachlorobiphenyl (PCB126), pulmonary alveolar epithelium at the junction of terminal bronchioles and along alveolar ducts was replaced by cuboidal to columnar ciliated cells. Scattered among these were cells exhibiting characteristics consistent with those of Clara cells; they lacked cilia and had a smooth apical surface that protruded into the alveolar space. This lesion was not typical of alveolar epithelial hyperplasia seen in rodent lungs; therefore, studies were done to characterize the lesion. Results of periodic acid-Schiff (PAS) staining, alcian blue (AB) staining, and GSTPi immunohistochemical staining of the lesions seen in treated rats were more similar to normal bronchiolar epithelium than normal alveolar epithelium or alveolar epithelial hyperplasia. These findings, along with the morphology of the cells, provide evidence that this lesion is closer in character to bronchiolar epithelium than alveolar type I or alveolar type II epithelium, and as a result, was called bronchiolar metaplasia.

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“…The AhR is expressed in lung epithelial cells, Clara cells, and ciliated cells (31,43; our unpublished observations). Moreover, exposure of mice to TCDD induced CYP 1A1, a hallmark indicator of AhR activation, in endothelial cells of capillaries and larger vessels in the lung, type II pneumocytes, Clara cells, and bronchoepithelial cells (3,27).…”

Section: Vol 74 2006 Ahr Activation In S Pneumoniae Infection 5683mentioning

confidence: 72%

Protection against Lethal Challenge withStreptococcus pneumoniaeIs Conferred by Aryl Hydrocarbon Receptor Activation but Is Not Associated with an Enhanced Inflammatory Response

Vorderstrasse

Lawrence

2006

Infect Immun

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Streptococcus pneumoniae is a common respiratory pathogen and a major cause of morbidity and mortality in humans, particularly in the elderly and young children. The pulmonary immune response to S. pneumoniae is initiated very rapidly, and, ideally, innate immune responses are able to contain bacterial colonization. In the studies presented here, we sought to determine whether activation of the aryl hydrocarbon receptor (AhR) would protect mice from an otherwise lethal infection with S. pneumoniae. The rationale for this hypothesis is that, although most AhR agonists are potent immunosuppressants, AhR activation enhances the inflammatory response to pathogenic and nonpathogenic stimuli. Specifically, neutrophil numbers and levels of inflammatory cytokines are often increased in mice treated with the potent AhR agonist 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD). To test the hypothesis, vehicle control-or TCDD-treated mice were intranasally infected with S. pneumoniae. Mortality, pulmonary bacterial burden, cytokine/chemokine levels, and influx of immune cells to the lung were analyzed at various times postinfection. As predicted, survival was substantially improved in the mice treated with TCDD, and the pulmonary bacterial burden was decreased. Surprisingly, however, there was no evidence suggesting that protection resulted from an enhanced inflammatory response. In fact, neutrophil numbers and inflammatory chemokines and cytokines were all decreased in the TCDD-treated mice relative to vehicle control-treated mice. This suggests that the protective effect of AhR activation is not the result of altered immune function but instead may reflect a direct effect on the response of lung cells to infection.

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Induction of Lung Lesions in Female Rats Following Chronic Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Cited by 22 publications

References 29 publications

TCDD Promotes Lung Tumors via Attenuation of Apoptosis through Activation of the Akt and ERK1/2 Signaling Pathways

TCDD Promotes Lung Tumors via Attenuation of Apoptosis through Activation of the Akt and ERK1/2 Signaling Pathways

Characterization of Bronchiolar Metaplasia of the Alveolar Epithelium in Female Sprague—Dawley Rats Exposed to 3,3',4,4',5-Pentachlorobiphenyl (PCB126)

Protection against Lethal Challenge withStreptococcus pneumoniaeIs Conferred by Aryl Hydrocarbon Receptor Activation but Is Not Associated with an Enhanced Inflammatory Response

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