Mechanisms of Exocrine Pancreatic Toxicity Induced by Oral Treatment with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Female Harlan Sprague-Dawley Rats

Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicological Sciences (Impact Factor: 3.85). 06/2005; 85(1):594-606. DOI: 10.1093/toxsci/kfi121
Source: PubMed


In previous 2-year studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) conducted by the National Toxicology Program on female Harlan Sprague-Dawley rats, acinar-cell vacuolation, atrophy, inflammation, and arteritis developed at high incidence, and a rare occurrence of pancreatic acinar-cell adenomas and carcinomas was noted. In this investigation, we sought to identify the mechanism involved in the early formative stages of acinar-cell lesions. Pancreas from animals treated for 14 and 31 weeks with 100 ng TCDD/kg body weight or corn oil vehicle was examined immunohistochemically and/or morphometrically. Acinar-cell kinetics were analyzed using staining with hematoxylin and eosin and proliferating cell nuclear antigen. Expressions of cytochrome P450 (CYP) 1A1 and aryl hydrocarbon receptor (AhR) were evaluated to assess direct effects of TCDD exposure. The cholecystokinin-A receptor (CCK-A receptor; CCKAR) and duodenal cholecystokinin 8 (CCK) revealed the associations of dioxin treatment with hormonal changes. Amylase localization showed acinar structural changes that could affect enzymatic production. Increased apoptotic activity in acinar cells occurred in 14- and 31-week-treated animals, with an increase in proliferative activity in the latter. Also in the latter, in the vacuolated acinar cells, CYP1A1 was overexpressed, and statistically significant decreases in expressions of AhR, CCKAR, and amylase occurred. The intensity of CCKAR expression increased in nonvacuolated acinar cells; a decrease in the size of CCK-positive epithelial cells occurred in duodenum. Our findings indicate that dioxin-induced acinar-cell lesions might be related to a direct effect of TCDD on the pancreas. Increase in CYP1A1 and decrease in CCKAR expressions in vacuolated acinar cells may be involved in the pathogenesis of pancreatic lesions. Changes in the expression of CYP or CCKAR may have induced the acinar-cell tumors by initiating proliferation.

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    • "However, the effects of PCBs on exocrine pancreas remain unclear. It has been reported that female Harlan Sprague-Dawley rats treated with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin and dioxin-like compounds including PCB126 for 2 years can result in cytoplasmic vacuolation, atrophy, inflammation and exocrine adenomas in the exocrine pancreas (Nyska et al., 2004; Yoshizawa et al., 2005). The extracellular signal-regulated kinase (ERK) signaling cascade is a central mitogen-activated protein kinase (MAPK) pathway that plays an important role in the regulation of various cellular processes including proliferation, differentiation , and apoptosis (Shaul and Seger, 2007). "
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    • "The action of DLC may, therefore, be a disruption of retinoid action leading to altered growth and differentiation of the lung epithelium resulting in squamous metaplasia and CKE. Of note was that in our studies, TCDD, PCB126, PeCDF, and TEF mixture affected the epithelial differentiation to squamous type; the induction of gingival squamous cell hyperplasia and/or SCC, endometrial squamous metaplasia and/or SCC, and squamous hyperplasia in forestomach (NTP 2004a, b, c, d; Yoshizawa et al., 2005). "
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