In Utero and Lactational Exposures to Low Doses of Polybrominated Diphenyl Ether-47 Alter the Reproductive System and Thyroid Gland of Female Rat Offspring

Background Polybrominated diphenyl ethers (PBDEs) are capable of disrupting thyroid hormone homeostasis. PBDE-47 (2,2′,4,4′-tetrabromodiphenyl ether) is one of the most abundant congeners found in human breast adipose tissue and maternal milk samples. Objectives We evaluated the effects of developmental exposure to low doses of PBDE-47 on the female reproductive system. Methods Pregnant Wistar rats were administered vehicle (peanut oil) or PBDE-47 [140 or 700 μg/kg body weight (bw)] on gestation day (GD) 6, or 5 mg 6-n-propyl-2-thiouracil (PTU)/L in the drinking water from GD7 through postnatal day (PND) 21. Results In female offspring sacrificed on PND38, there was a significant decrease in ovarian weight after exposure to PTU or 140 μg/kg PBDE-47. Alterations in folliculogenesis were apparent: we observed a decrease in tertiary follicles and serum estradiol concentrations in the offspring exposed to either PTU or 700 μg/kg PBDE-47. PTU exposure also resulted in a decrease in primordial follicles. On PND100, persistent effects on the thyroid glands included histologic and morphometric changes after exposure to either PTU or PBDE-47. No relevant changes in reproductive indices were observed after mating the exposed F1 females with nontreated males. Conclusions Administration of PBDE-47 at doses relevant to human exposure led to changes in the rat female reproductive system and thyroid gland.

[1]  M. Shakibaei,et al.  Ultrastructural changes observed in rat ovaries following in utero and lactational exposure to low doses of a polybrominated flame retardant. , 2005, Toxicology letters.

[2]  S. Wakui,et al.  Mammary gland differentiation in female rats after prenatal exposure to 3,3',4,4',5-pentachlorobiphenyl. , 2002, Toxicology.

[3]  K A Thayer,et al.  Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[4]  T. Pedersen,et al.  Proposal for a classification of oocytes and follicles in the mouse ovary. , 1968, Journal of reproduction and fertility.

[5]  Adrian Covaci,et al.  Investigation of selected persistent organic pollutants in farmed Atlantic salmon (Salmo salar), salmon aquaculture feed, and fish oil components of the feed. , 2002, Environmental science & technology.

[6]  H. Matsuo,et al.  The role of thyroid hormone as a biological amplifier of the actions of follicle-stimulating hormone in the functional differentiation of cultured porcine granulosa cells. , 1987, Endocrinology.

[7]  R C Hale,et al.  Polybrominated diphenyl ether flame retardants in Virginia freshwater fishes (USA). , 2001, Environmental science & technology.

[8]  J. Furr,et al.  In vivo and in vitro anti-androgenic effects of DE-71, a commercial polybrominated diphenyl ether (PBDE) mixture. , 2005, Toxicology and applied pharmacology.

[9]  J. Flaws,et al.  Methoxychlor may cause ovarian follicular atresia and proliferation of the ovarian epithelium in the mouse. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[10]  R. L. Santos,et al.  Histomorphometry and Quantification of Nucleolar Organizer Regions in Bovine Thyroid Containing Methylthiouracil Residues , 1999, Veterinary pathology.

[11]  D. Pfaff,et al.  Estrogen and thyroid hormone receptor interactions: physiological flexibility by molecular specificity. , 2002, Physiological reviews.

[12]  A. Doufas,et al.  The Hypothalamic‐Pituitary‐Thyroid Axis and the Female Reproductive System , 1997, Annals of the New York Academy of Sciences.

[13]  I. Chahoud,et al.  Developmental Exposure to Low-Dose PBDE-99: Effects on Male Fertility and Neurobehavior in Rat Offspring , 2004, Environmental health perspectives.

[14]  Eva Jakobsson,et al.  Neurobehavioral derangements in adult mice receiving decabrominated diphenyl ether (PBDE 209) during a defined period of neonatal brain development. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[15]  C. Rice,et al.  Comparisons of PBDE composition and concentration in fish collected from the Detroit River, MI and Des Plaines River, IL. , 2002, Chemosphere.

[16]  N. Kerkvliet,et al.  Immunologic and endocrine effects of the flame-retardant pentabromodiphenyl ether (DE-71) in C57BL/6J mice. , 1994, Toxicology.

[17]  R. Hutz,et al.  Modulation of ovarian follicle maturation in Long-Evans rats exposed to polychlorinated biphenyls (PCBs) in-utero and lactationally. , 2003, Reproductive toxicology.

[18]  Arnold Schecter,et al.  Polybrominated diphenyl ethers (PBDEs) in U.S. mothers' milk. , 2003, Environmental health perspectives.

[19]  K M Crofton,et al.  Effects of short-term in vivo exposure to polybrominated diphenyl ethers on thyroid hormones and hepatic enzyme activities in weanling rats. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[20]  Boris Johnson-Restrepo,et al.  Polybrominated diphenyl ethers and polychlorinated biphenyls in human adipose tissue from New York. , 2005, Environmental science & technology.

[21]  M. van den Berg,et al.  Inhibition and induction of aromatase (CYP19) activity by brominated flame retardants in H295R human adrenocortical carcinoma cells. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[22]  H. Leffers,et al.  Dual effects of phytoestrogens result in u-shaped dose-response curves. , 2002, Environmental health perspectives.

[23]  Kevin M Crofton,et al.  Assessment of DE-71, a commercial polybrominated diphenyl ether (PBDE) mixture, in the EDSP male and female pubertal protocols. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[24]  K. Norén,et al.  Analysis of polybrominated diphenyl ethers in Swedish human milk. A time-related trend study, 1972-1997. , 1999, Journal of toxicology and environmental health. Part A.

[25]  S. Grande,et al.  Effects of Developmental Exposure to 2,2′,4,4′,5-Pentabromodiphenyl Ether (PBDE-99) on Sex Steroids, Sexual Development, and Sexually Dimorphic Behavior in Rats , 2005, Environmental health perspectives.

[26]  J. Lay,et al.  Postnatal exposure of the male mouse to 2,2',3,3',4,4',5,5',6,6'-decabrominated diphenyl ether: decreased epididymal sperm functions without alterations in DNA content and histology in testis. , 2006, Toxicology.

[27]  Kevin M Crofton,et al.  Developmental exposure to brominated diphenyl ethers results in thyroid hormone disruption. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[28]  G. Prins,et al.  Neonatal Low- and High-Dose Exposure to Estradiol Benzoate in the Male Rat: II. Effects on Male Puberty and the Reproductive Tract , 2001, Biology of reproduction.

[29]  Ronald A Hites,et al.  Polybrominated diphenyl ethers in the environment and in people: a meta-analysis of concentrations. , 2004, Environmental science & technology.

[30]  Salomon Sand,et al.  Dose-response modeling and benchmark calculations from spontaneous behavior data on mice neonatally exposed to 2,2',4,4',5-pentabromodiphenyl ether. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[31]  Nathan G Dodder,et al.  Polybrominated diphenyl ethers in maternal and fetal blood samples. , 2003, Environmental health perspectives.

[32]  E. Jakobsson,et al.  A brominated flame retardant, 2,2',4,4',5-pentabromodiphenyl ether: uptake, retention, and induction of neurobehavioral alterations in mice during a critical phase of neonatal brain development. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[33]  I. Meerts,et al.  In vitro estrogenicity of polybrominated diphenyl ethers, hydroxylated PDBEs, and polybrominated bisphenol A compounds. , 2001, Environmental health perspectives.

[34]  A. Gerecke,et al.  Polybrominated diphenyl ethers in whitefish from Swiss lakes and farmed rainbow trout. , 2003, Chemosphere.

[35]  E. Jakobsson,et al.  Brominated flame retardants: a novel class of developmental neurotoxicants in our environment? , 2001, Environmental health perspectives.

[36]  W. Lichtensteiger,et al.  Developmental exposure of rats to a reconstituted PCB mixture or aroclor 1254: effects on organ weights, aromatase activity, sex hormone levels, and sweet preference behavior. , 1999, Toxicology and applied pharmacology.

[37]  S. Fujii,et al.  Large-scale evaluation of the current level of polybrominated diphenyl ethers (PBDEs) in breast milk from 13 regions of Japan. , 2006, Chemosphere.

[38]  P. Hoyer,et al.  Ultrastructural Evaluation of Oocytes During Atresia in Rat Ovarian Follicles1 , 2000, Biology of reproduction.

[39]  C. Keen,et al.  Polybrominated diphenyl ether (PBDE)-induced alterations in vitamin A and thyroid hormone concentrations in the rat during lactation and early postnatal development. , 2006, Toxicology and applied pharmacology.

[40]  C. D. de Wit,et al.  Higher brominated diphenyl ethers and hexabromocyclododecane found in eggs of peregrine falcons (Falco peregrinus) breeding in Sweden. , 2004, Environmental science & technology.

[41]  E R Weibel,et al.  Recent stereological methods for cell biology: a brief survey. , 1990, The American journal of physiology.

[42]  N. Bunce,et al.  Polybrominated diphenyl ethers as Ah receptor agonists and antagonists. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[43]  G. Stancel,et al.  Regulation of the uterine response to estrogen by thyroid hormone. , 1978, Endocrinology.

[44]  A. K. Peters,et al.  Interactions of polybrominated diphenyl ethers with the aryl hydrocarbon receptor pathway. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[45]  P. Darnerud,et al.  Effects of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) on thyroid hormone and vitamin A levels in rats and mice , 2001, Archives of Toxicology.

[46]  Anders Fredriksson,et al.  Neonatal exposure to higher brominated diphenyl ethers, hepta-, octa-, or nonabromodiphenyl ether, impairs spontaneous behavior and learning and memory functions of adult mice. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[47]  Anders Fredriksson,et al.  Investigations of strain and/or gender differences in developmental neurotoxic effects of polybrominated diphenyl ethers in mice. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[48]  E W Carney,et al.  Evaluation of the EDSTAC female pubertal assay in CD rats using 17beta-estradiol, steroid biosynthesis inhibitors, and a thyroid inhibitor. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[49]  L. Driscoll,et al.  Brief postnatal PBDE exposure alters learning and the cholinergic modulation of attention in rats. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[50]  D. D. de Rooij,et al.  Effect of hypothyroidism on ovarian follicular development, granulosa cell proliferation and peripheral hormone levels in the prepubertal rat. , 1996, European journal of endocrinology.

[51]  Robin J Law,et al.  Levels of polybrominated diphenyl ether (PBDE) flame retardants in animals representing different trophic levels of the North Sea food Web. , 2002, Environmental science & technology.

[52]  W. Chan,et al.  Effect of hypothyroidism induced by propylthiouracil and thiourea on male and female reproductive systems of neonatal mice. , 1995, The Journal of experimental zoology.

[53]  M. Schlumpf,et al.  Gene expression and estrogen sensitivity in rat uterus after developmental exposure to the polybrominated diphenylether PBDE 99 and PCB. , 2006, Toxicology.

[54]  N. Bunce,et al.  Synthesis of polybrominated diphenyl ethers and their capacity to induce CYP1A by the Ah receptor mediated pathway. , 2001, Environmental science & technology.

[55]  G. Prins,et al.  Neonatal Low- and High-Dose Exposure to Estradiol Benzoate in the Male Rat: I. Effects on the Prostate Gland1 , 2001, Biology of reproduction.

[56]  Rajiv Bhatia,et al.  High body burdens of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in California women. , 2003, Environmental health perspectives.

[57]  M. Cunningham,et al.  Differential expression of CYP1A, 2B, and 3A genes in the F344 rat following exposure to a polybrominated diphenyl ether mixture or individual components. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[58]  C. Rochette-Egly.  Nuclear receptors: integration of multiple signalling pathways through phosphorylation. , 2003, Cellular signalling.

[59]  R. Lang-Roth,et al.  Allgemeine und spezielle Pharmakologie und Toxikologie , 2009 .

[60]  G. M. Richardson,et al.  Is house dust the missing exposure pathway for PBDEs? An analysis of the urban fate and human exposure to PBDEs. , 2005, Environmental science & technology.

[61]  R. Hutz,et al.  In utero and lactational exposure of Long-Evans rats to ammonium perchlorate (AP) disrupts ovarian follicle maturation. , 2004, Reproductive toxicology.