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.
"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). "
"In these studies, an increase occurred in the incidence of squamous cell tumors, such as squamous cell carcinoma (SCC) of the oral cavity and/or uterus, and cystic keratinizing epithelioma of the lung (NTP 2004a, 2004g; Walker et al. 2005; Walker et al. 2007; Yoshizawa, Walker et al. 2005). Moreover , administration of these DLCs caused increased incidence of nonneoplastic lesions in multiple organs, including the reproductive system (Brix et al. 2004; Jokinen et al. 2003; Nyska et al. 2004; Nyska et al. 2005; Tani et al. 2004; Yoshizawa, Marsh et al. 2005; Yoshizawa, Walker et al. 2005; Yoshizawa et al. 2007). "
[Show abstract][Hide abstract] ABSTRACT: Results from previously published animal studies suggest that prenatal and postnatal exposure to dioxin and dioxin-like compounds (DLCs) may profoundly affect the reproductive system of both sexes via endocrine disruption. In the present work, we evaluate the toxicity and carcinogenicity of various DLCs, with an emphasis on their effect on the reproductive organs, induced by chronic exposure of female adult Harlan Sprague-Dawley rats. This investigation represents part of an initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. For fourteen, thirty-one, or fifty-three weeks or for two years, animals were administered by gavage 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); 2,3',4,4',5-pentachlorobiphenyl (PCB118); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and PCB118. The ranges of treatment-related changes in the reproductive system included chronic active inflammation in the ovary that occurred in the 1,000 and 3,000 microg/kg core groups (two-year exposure) of PCB153 and in the 300 ng/3,000 microg/kg core group of binary mixture of PCB126 and PCB153. Increases in the incidence of acute and/or chronic active inflammation of the uterus were observed in all dosed groups, including the stop-exposure group (withdrawal after thirty-week exposure) of PeCDF and the 1,000 microg/kg and/or higher group dosed with PCB153. The incidence of cystic endometrial hyperplasia was marginally increased in the 92 PeCDF ng/kg group at two years. The incidence of squamous metaplasia was significantly increased in the 44 ng/kg and higher dose group, including the stop-exposure group. The incidence of uterine squamous cell carcinoma was significantly or marginally increased in the 6 ng/kg core and 100 ng/kg stop-exposure groups of TCDD and in the 300 ng/300 microg/kg core group that received the binary mixture of PCB126 and 153. The incidence of uterine carcinoma was marginally increased in the 92 ng/kg PeCDF group at two years and clearly increased in the 1,000 and 4,600 microg/kg PCB118 core group and the 4,600 microg/kg stop group. In the studies of PCB 126, the tertiary mixture, and the binary mixture of PCB126 and PCB118, no increased incidence of any change occurred in the reproductive systems. The range of changes seen with the different compounds suggests that more than one mechanism may have been involved in promoting the female reproductive pathology.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Dioxin and dioxin-related compounds have been associated with high incidences of pulmonary dysfunctions and/or cancers in humans. To evaluate the relative potencies of effects of these compounds, the National Toxicology Program completed a series of two-year bioassays which were conducted using female Harlan Sprague-Dawley rats. The rats were treated orally for up to 2 years with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and a ternary mixture of TCDD, PCB126 and PeCDF. In addition to treatment-related effects reported in other organs, a variety of pulmonary lesions were observed that were related to exposure. Pulmonary CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was increased in all dosed groups. The most common non-neoplastic lesions, which occurred in all studies, were bronchiolar metaplasia and squamous metaplasia of the alveolar epithelium. Cystic keratinizing epithelioma was the most commonly observed neoplasm which occurred in all studies. A low incidence of squamous cell carcinoma was associated only with PCB126 treatment. Potential mechanisms leading to altered differentiation and/or proliferation of bronchiolar and alveolar epithelia may be through CYP1A1 induction or disruption of retinoid metabolism.
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