Assessment of DE-71, a Commercial Polybrominated Diphenyl Ether (PBDE) Mixture, in the EDSP Male and Female Pubertal Protocols

Abstract

DE-71, a commercial mixture, was used to test the sensitivity of the female and male pubertal protocol to detect thyroid active chemicals. These protocols are being evaluated for the U.S. EPA's Endocrine Disruptor Screening Program as part of a Tier I Screening Battery. To examine the ability of these protocols to screen for chemicals that induce the clearance of thyroid hormone, we examined male and female Wistar rats following DE-71 exposure. Rats were gavaged daily with 0, 3, 30, or 60 mg/kg DE in corn oil from postnatal day (PND) 23-53 in the male or PND 22-41 in the female. The temporal effects of DE-71 on liver enzymes and thyroid hormones were measured in another group of males and females following only 5 days of dosing (PND 21 to 26 in females and PND 23 to 28 in males). Serum T4 was significantly decreased at 30 and 60 mg/kg following the 5-day exposures and in the 21-day exposed females. Doses of 3, 30, and 60 mg/kg decreased T4 in 31-day exposed males. Serum T3 was decreased and TSH elevated by 30 and 60 mg/kg in the 31-day exposed males only. Decreased colloid area and increased follicular cell heights (indicative of the hypothyroid state) were observed in thyroids of the 60 mg/kg groups of 20- and 31-day exposed female and males. Increased liver-to-body weight ratios coincided with a significant induction of uridinediphosphate-glucuronosyltransferase (UDGPT; two to four-fold), and ethoxy- and pentoxy-resorufin-O-deethylase (EROD and PROD) at the two highest doses in all exposures. Of the androgen dependent tissues in the 31-day exposed males, seminal vesicle (SV) and ventral prostate (VP) weights were reduced at 60 mg/kg, while testes and epididymal weights were not affected. Preputial separation (PPS) was also significantly delayed by doses of 30 and 60 mg/kg. In the female, the 60 mg/kg dose also caused a significant delay in the age of vaginal opening. Based upon the thyroid hormone response data, this study provides evidence that the 31-day alternative Tier 1 male protocol is a more sensitive test protocol than the 5-day or female pubertal protocol for thyrotoxic agents that act via up-regulation of hepatic metabolism. This apparent greater sensitivity may be due a greater body burden attained following the longer dosing regimen as compared with that of the female protocol, or to gender specific differences in thyroid hormone metabolism. Also, the delay in PPS and reduction in SV and VP weights may indicate a modification or inhibition of endogenous androgenic stimulation directly by DE-71 or a secondary effect that occurs in response to a DE-induced change in thyroid hormones.

Thyroid disruption by technical decabromodiphenyl ether (DE-83R) at low concentrations in Xenopus laevis

“…In previous studies, increased incidences of thyroid follicular cell hyperplasia as well as follicular cell adenomas and carcinomas were observed in decaBDE-treated mice (NTP, 1986). Decreased colloid area and increased follicular cell heights were observed in commercial pentaBDE mixture (DE-71) treated rats (Stoker et al, 2004). In the present study, we found that technical decaBDE DE-83R at 1, 10, and 100 ng/L resulted in multilayer follicular epithelial cell, while it at 1000 ng/L caused a increase in follicle size accompanied by partial colloid depletion and a increase in the peripheral colloid vacuolation.…”

Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents

“…Although both fetal and early postnatal periods of exposure fall into the so-called "programming window", there may be differences in sensitivity to endocrine disruption even within this particular period. The dose of EDC plays a critical role since, when investigated at a given period of life, higher doses appear to be more effective such as shown after prenatal exposure for DDE (Loeffler and Peterson, 1999) and phthalates (Saillenfait et al, 2008;Salazar et al, 2004), or after lactational exposure for DDE, vinclozolin or DES (Yoshimura et al, 2005) or following exposure after weaning for DDE (Ashby and Lefevre, 2000;Yoshimura et al, 2005), vinclozolin (Yoshimura et al, 2005;Monosson et al, 1999), DES (Yoshimura et al, 2005;Shin et al, 2009), phthalates (Ge et al, 2007;Noriega et al, 2009) and PBDE (Stoker et al, 2004). It is noteworthy that in two studies using phthalates, opposing effects are observed since lower doses are associated with early puberty and higher doses with delayed puberty (Ge et al, 2007;Saillenfait et al, 2008).…”

“…Here, the complexity of neuroendocrine mechanisms appears since, in conditions causing early puberty, the arcuate nucleus expression of Kiss1 mRNA and kisspeptin protein is increased but the receptor GPR54 mRNA expression is reduced (Hu et al, 2013;Ma et al, 2006). Polybromi-nated EDCs appear to cause either no change or delay in VO depending on the dose and irrespective of the period of exposure (Stoker et al, 2004;Lilienthal et al, 2006;Ceccatelli et al, 2006). A similar conclusion can be drawn using DDT though there are no data after prenatal exposure.…”

Exposure to DE-71 alters thyroid hormone levels and gene transcription in the hypothalamic–pituitary–thyroid axis of zebrafish larvae

“…For instance, exposure to commercial PBDE mixtures in rat pups during pre-pubertal (Zhou et al, 2002;Ellis-Hutchings et al, 2006) and pubertal stages (Zhou et al, 2001) resulted in a decrease in the concentrations of circulating TH. Oral intake of commercial PBDE (DE-71) decreased plasma TH levels and induced marked thyroid hyperplasia in rats (Stoker et al, 2004). Recent reports suggest that oral administration of BDE-47 to mice (Richardson et al, 2008) and perinatal exposure of DE-71 to male rat pups caused significant reduction of thyroxine (T4) (Szabo et al, 2009).…”