Comparative Toxicogenomic Examination of the Hepatic Effects of PCB126 and TCDD in Immature, Ovariectomized C57BL/6 Mice

Kopec, Anna K.; Boverhof, Darrell R.; Burgoon, Lyle D.; Ibrahim-Aibo, Daher; Harkema, Jack R.; Tashiro, Colleen; Chittim, Brock; Zacharewski, Timothy R.

doi:10.1093/toxsci/kfm289

Cited by 34 publications

(46 citation statements)

References 41 publications

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“…In detail, only three bacterial families including Methanosaetaceae , Erysipelotrichaceae , and a group from clostridia were significantly reduced ( p < 0.05) in mice dosed with CO. In our previous studies using sesame oil—a common vehicle (Brown et al 1998; Kopec et al 2008), we observed a response that opposed TCDD in terms of shifting SFB, Firmicutes , and Enterobacteriaceae (Bhaduri 2015; Stedtfeld et al 2017, submitted). For example, compared to the relative abundance 1 day before dosing, Enterobacteriaceae in fecal pellets decreased ~ 10-fold and 300-fold, 3 and 7 days following an initial dose of sesame oil, respectively.…”

Section: Resultsmentioning

confidence: 94%

TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal

Stedtfeld¹,

Sallach

Crawford

et al. 2017

Appl Microbiol Biotechnol

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Activated carbon (AC) is an increasingly attractive remediation alternative for the sequestration of dioxins at contaminated sites globally. However, the potential for AC to reduce the bioavailability of dioxins in mammals and the residing gut microbiota has received less attention. This question was partially answered in a recent study examining 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced hallmark toxic responses in mice administered with TCDD sequestered by AC or freely available in corn oil by oral gavage. Results from that study support the use of AC to significantly reduce the bioavailability of TCDD to the host. Herein, we examined the bioavailability of TCDD sequestered to AC on a key murine gut commensal and the influence of AC on the community structure of the gut microbiota. The analysis included qPCR to quantify the expression of segmented filamentous bacteria (SFB) in the mouse ileum, which has responded to TCDD-induced host toxicity in previous studies and community structure via sequencing the 16S ribosomal RNA (rRNA) gene. The expression of SFB 16S rRNA gene and functional genes significantly increased with TCDD administered with corn oil vehicle. Such a response was absent when TCDD was sequestered by AC. In addition, AC appeared to have a minimal influence on murine gut community structure and diversity, affecting only the relative abundance of Lactobacillaceae and two other groups. Results of this study further support the remedial use of AC for eliminating bioavailability of TCDD to host and subsequent influence on the gut microbiome.

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Section: Resultsmentioning

confidence: 94%

TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal

Stedtfeld¹,

Sallach

Crawford

et al. 2017

Appl Microbiol Biotechnol

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“…Animal studies were performed as previously described (Boverhof et al, 2005; Kopec et al, 2008). In short, immature female C57BL/6 ovariectomized (ovx) mice (post natal day 25, Charles River Laboratories, Portage, MI) were housed at 23 °C with 30–40% humidity and 12-h light/dark cycle.…”

Section: Methodsmentioning

confidence: 99%

“…Mice were fed Harlan Teklad 22/5 Rodent Diet 8640 (Madison, WI) ad libitum and had free access to deionized water. Mice were acclimated for 3 days, and then orally gavaged once with 30 µg/kg TCDD (Boverhof et al, 2005), 300 µg/kg PCB126 (Kopec et al, 2008), 90 mg/kg βNF, or sesame oil (vehicle). The PCB126 dose was chosen based on its toxic equivalency factor (TEF) of 0.1, while doses ≥80 mg/kg βNF elicit maximal hydroxylase activity (Boobis et al, 1977).…”

Section: Methodsmentioning

confidence: 99%

“…In order to examine if AhR ligands which activates the canonical AhR pathway demonstrate selective modulation, differential gene expression elicited TCDD, PCB126, β-naphthoflavone (βNF), and indolo-[3,2b]-carbazole (ICZ) was examined in mouse Hepa1c1c7 cells and C57BL/6 liver samples. Although each ligand exhibits high AhR binding affinity, Cyp1a1 mRNA induction and the induction of aryl hydrocarbon hydroxylase activity (Boobis et al, 1977; Chen et al, 1995, 2010; Denison and Nagy, 2003; Denison et al, 2011; Kopec et al, 2008; Pohjanvirta et al, 2002), they are structurally diverse with different metabolism kinetics. Therefore, global gene expression profiles were compared not only to identify conserved differential expression but also to investigate divergent and ligand-specific gene expression changes suggestive of SAhRM activity.…”

Section: Introductionmentioning

confidence: 99%

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Comparisons of differential gene expression elicited by TCDD, PCB126, βNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver

et al. 2013

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The aryl hydrocarbon receptor (AhR) is a promiscuous receptor activated by structurally diverse synthetic and natural compounds. AhR activation may lead to ligand-specific changes in gene expression despite similarities in mode of action. Therefore, differential gene expression elicited by four structurally diverse, high affinity AhR ligands (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 nM, 30 µg/kg), 3,3′,4,4′,5-pentachlorobiphenyl (PCB126; 100 nM, 300 µg/kg), β-naphthoflavone (βNF; 10 µM, 90 mg/kg), and indolo[3,2-b]carbazole (ICZ; 1 µM)) in mouse Hepa1c1c7 hepatoma cells and C57BL/6 mouse liver samples were compared. A total of 288, 183, 119, and 131 Hepa1c1c7 genes were differentially expressed (|fold-change| ≥ 1.5, P1(t) ≥ 0.9999) by TCDD, βNF, PCB126, and ICZ, respectively. Only ~35% were differentially expressed by all 4 ligands in Hepa1c1c7 cells. In vivo, 661, 479, and 265 hepatic genes were differentially expressed following treatment with TCDD, βNF, and PCB126, respectively. Similar to Hepa1c1c7 cells, ≤34% of gene expression changes were common across all ligands. Principal components analysis identified time-dependent gene expression divergence. Comparisons of ligand-elicited expression between Hepa1c1c7 cells and mouse liver identified only 11 common gene expression changes across all ligands. Although metabolism may explain some ligand-specific gene expression changes, PCB126, βNF, and ICZ also elicited divergent expression compared to TCDD, suggestive of selective AhR modulation.

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“…The effects on genes of the steroideogenic pathway relate to the deregulation of cholesterol homeostasis. Observed the inhibition of beta-oxidation, indicating impaired lipid metabolism [63][64][65]. Exposures of dibutyl phthalate were examined in male and female F344/N rats and B6C3F1 mice in 13-week feed studies.…”

Section: Toxicogenomics and Clinical Mechanismsmentioning

confidence: 99%

Toxicogenomics and cancer pathogenesis

Gupta¹,

AK²,

Boraste³

et al. 2009

Int J Genet

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Abstract-Toxicogenomics is emerging field give idea of the application of large-scale differential gene expression data to toxicology, starting to influence drug discovery and development in the pharmaceutical industry. Its future potential in cancer pathogenesis, study of poisons and poisoning and has an ancient and venerable history. Toxicogenomics is the merging of toxicology with technologies that have been developed, together with bioinformatics, to identify and quantify global gene expression changes for gene therapy. Immunotoxic processes and the development of in vitro screening assays is therefore expected to be of value for mechanistic insight into immunotoxicity and hazard identification of existing and novel compounds. Successful application of toxicogenomic approaches, such as DNA microarrays, inextricably relies on appropriate data management, the ability to extract knowledge from massive amounts of data and the availability of functional information for data interpretation. Toxicogenomics is considered a valuable tool for reducing pharmaceutical candidate attrition by facilitating earlier identification, prediction and understanding of toxicities. Pharmaco-epidemiological (toxicogenomics) data is now available for both antiepileptic drugs, evidence for human carcinogenicity. Therapeutic researches converge triad of rejuvenation, regeneration or replacement strategies that rely on self-healing processes, stem cell regeneration organ transplantation. Metastases studies usually display more genetic changes than the primary tumour. Helix-loop-helix application in translational and functional toxicogenomics transcription factors has been implicated in diverse cellular processes such as proliferation, apoptosis, differentiation, and migration.

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Comparative Toxicogenomic Examination of the Hepatic Effects of PCB126 and TCDD in Immature, Ovariectomized C57BL/6 Mice

Cited by 34 publications

References 41 publications

TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal

TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal

Comparisons of differential gene expression elicited by TCDD, PCB126, βNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver

Toxicogenomics and cancer pathogenesis

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