Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

Abstract

We studied the effect of administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by i.p. injection once every two weeks in combination with a high-fat (HF) diet for 8 or 16 weeks on the body and organ weight changes as well as on the hepatic enzyme activity for estrogen metabolism in C3H/HeN female mice. Administration of TCDD at 100 μg/kg b.w. once every two weeks for 8 weeks increased the body weight by 46% in the HF diet-fed animals, but not in the regular diet-fed animals. This is the first observation suggesting that TCDD, a potent Ah receptor agonist, may have an obesity-inducing effect in animals fed a HF diet. While TCDD increased liver weight and decreased thymus weight in animals, these effects were enhanced by feeding animals a HF diet. Metabolism studies showed that TCDD administration for 8 or 16 weeks increased the liver microsomal activity for the 2-and 4-hydroxylation of 17β-estradiol in animals fed a control diet, but surprisingly not in animals fed a HF diet. Treatment with TCDD dose-dependently increased the hepatic activity for the O-methylation of catechol estrogens in both control and HF diet-fed animals, and it also decreased the levels of liver microsomal sulfatase activity for hydrolysis of estrone-3-sulfate. TCDD did not significantly affect the hepatic enzyme activity for the glucuronidation or esterification of endogenous estrogens. It is suggested that enhanced metabolic inactivation of 1 This study was supported, in part, by a grant from the American Cancer Society (RSG-02-143-01-CNE to BTZ) and also by grants from the NIH (CA92391, CA97109 and ES05022). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. endogenous estrogens by hepatic estrogen-metabolizing enzymes in TCDD-treated, control diet-fed animals contributes importantly to the reduced incidence of estrogen-associated tumors in animals treated with TCDD. NIH Public Access

Toxicological Function of Adipose Tissue: Focus on Persistent Organic Pollutants

“…Zhu et al (2008) reported that body weights of adult C3H/HeN mice exposed to 100 µg TCDD/kg body weight once every 2 weeks for 8 weeks were > 40% higher than those of control mice. This body weight change was seen only when mice were fed a high fat diet, which was not out of the range of an American diet.…”

Adipocytes under assault: Environmental disruption of adipose physiology

“…Low dose DES exposure resulted in increased body weight in the postnatal period, while high dose exposure resulted in reduced body weight; in contrast, high dose exposure to DDT in utero led to elevated body weight, whereas lower dose exposure reduced body weight [153]. Likewise, TCDD has been shown to induce wasting at higher doses of exposure [154], while lower doses result in weight gain [155]. Whether these divergent effects result from alterations in the responsiveness of the same signal transduction cascade or represent activation/inhibition of different pathways at different concentrations requires further investigation.…”

“…The connection between dietary fat and chemical exposure was first shown in 1974 when male rats exposed to the plasticizer DEHP only exhibited augmented body weight gain and adiposity when fat was present in the diet [158]. Interestingly, exposure of mice to TCDD, most often associated with anorexigenic and wasting effects [154], results in significantly increased body weight if the animals are also fed a high-fat diet [155]. Because of the clear role that the “Western” diet plays in the obesity epidemic, understanding how EDCs interact with caloric excess to promote metabolic disruption is critical for characterizing potential synergy among the various factors that comprise an obesogenic environment.…”

Diabetes, Metabolic Syndrome, and Obesity in Relation to Serum Dioxin Concentrations: The Seveso Women’s Health Study

“…Experimental studies support a link between TCDD exposure and metabolic alterations. TCDD exposure has been associated with wasting syndrome in rodents fed a normal diet (Seefeld et al 1984), and with accelerated weight gain in mice fed a high-fat diet (Zhu et al 2008). Effects on glucose homeostasis have also been reported based on in vivo and in vitro studies, including reduced glucose uptake in adipose tissue, liver, and pancreas; altered glucose tolerance; and impaired insulin secretion (Enan and Matsumura 1993; Enan et al 1992a, 1992b; Ishida et al 2005; Kurita et al 2009).…”