Reproductive Lesions in Female Harlan Sprague-Dawley Rats Following Two-Year Oral Treatment with Dioxin and Dioxin-like Compounds

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.

Exposure to endocrine disruptors during adulthood: consequences for female fertility

“…Acute and chronic TCDD exposure (100 ng/kg/day) induced uterine tissue inflammation and increased the incidence of uterine lesions in rats (Yoshizawa et al 2009). TCDD (30 μg/kg) also caused anti-uterotrophic effects in ovariectomized mice by inhibiting estrogen-mediated gene expression (Boverhof et al 2008).…”

“…Chronic oral exposure to PCB congeners (1,000 and 4,600 μg/kg) is associated with an increased incidence of uterine squamous cell carcinoma in adult female rats (NTP 2010; Yoshizawa et al 2009). Chronic oral exposure to PCBs (300 ng/kg – 3,000 μg/kg) also induced chronic active inflammation in rat uteri (Yoshizawa et al 2009). A study of bovine reproductive tissues found that PCB exposure (1 – 100 ng/mL) increased myometrial contractility in vitro (Kotwica et al 2006).…”

Endocrine Disrupting Chemicals and Endometrial Cancer: An Overview of Recent Laboratory Evidence and Epidemiological Studies

“…On the other hand, Yoshikawa et al [55] performed an in vivo study where female adult Harlan Sprague-Dawley rats were exposed for 14, 31 and 53 weeks or for two years to different EDCs including PCBs (3,3’,4,4’,5 pentachlorobiphenyl (PCB 126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2’,4,4’,5,5’-hexachlorobiphenyl (PCB 153); 2,3’,4,4’,5-pentachlorobiphenyl (PCB 118) a binary mixture of PCB 126 and 153; or a binary mixture of PCB 126 and PCB 118) and resulted in an increasing of uterine squamous cell carcinoma uterine squamous cell carcinoma in the 300 ng/300 μg/kg core group that received the binary mixture of PCB 126 and 153 and in a clearly increasing incidence of uterine carcinoma in the 1000 and 4600 μg/kg PCB 118 core group and the 4600 μg/kg stop group.…”

“…Of relevance had been the study of Yoshizawa et al [55] where female adult Harlan Sprague-Dawley rats were exposed for 14, 31 and 53 weeks or for two years to different EDCs including 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) resulting in a marginally or significantly increasing of uterine squamous cell carcinoma, respectively, in the 6 ng/kg core and 100 ng/kg stop-exposure groups (Table 4). …”

Dioxin induction of transgenerational inheritance of disease in zebrafish

“…Direct exposure to TCDD leads to infertility in many vertebrate species, including humans, and is associated with down-regulation of enzymes in the estrogen synthesis pathway, decreased egg release, increased number of atretic ovarian follicles, and decreased fertilization success (DeVito and Birnbaum, 1994; King-Heiden et al , 2006; Yoshizawa et al , 2009; King-Heiden et al , 2012; Baker et al , 2013). Toxicity in adults following TCDD exposure during early development suggests that physiologic systems are being mis-programmed and that exposure to TCDD can potentially initiate irreversible and permanent modifications in gene expression and cell lineages.…”