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      Effects of Chronic Exposure to an Environmentally Relevant Mixture of Brominated Flame Retardants on the Reproductive and Thyroid System in Adult Male Rats

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          Abstract

          Brominated flame retardants (BFRs) are incorporated into a wide variety of consumer products, are readily released into home and work environments, and are present in house dust. Studies using animal models have revealed that exposure to polybrominated diphenyl ethers (PBDEs) may impair adult male reproductive function and thyroid hormone physiology. Such studies have generally characterized the outcome of acute or chronic exposure to a single BFR technical mixture or congener but not the impact of environmentally relevant BFR mixtures. We tested whether exposure to the BFRs found in house dust would have an adverse impact on the adult male rat reproductive system and thyroid function. Adult male Sprague Dawley rats were exposed to a complex BFR mixture composed of three commercial brominated diphenyl ethers (52.1% DE-71, 0.4% DE-79, and 44.2% decaBDE-209) and hexabromocyclododecane (3.3%), formulated to mimic the relative congener levels in house dust. BFRs were delivered in the diet at target doses of 0, 0.02, 0.2, 2, or 20 mg/kg/day for 70 days. Compared with controls, males exposed to the highest dose of BFRs displayed a significant increase in the weights of the kidneys and liver, which was accompanied by induction of CYP1A and CYP2B P450 hepatic drug–metabolizing enzymes. BFR exposure did not affect reproductive organ weights, serum testosterone levels, testicular function, or sperm DNA integrity. The highest dose caused thyroid toxicity as indicated by decreased serum thyroxine (T4) and hypertrophy of the thyroid gland epithelium. At lower doses, the thickness of the thyroid gland epithelium was reduced, but no changes in hormone levels (T4 and thyroid-stimulating hormone) were observed. Thus, exposure to BFRs affected liver and thyroid physiology but not male reproductive parameters.

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          An overview of commercially used brominated flame retardants, their applications, their use patterns in different countries/regions and possible modes of release.

          Brominated flame retardants (BFRs) are used in a variety of consumer products and several of those are produced in large quantities. These compounds have been detected in environmental samples, which can be attributed to the anthropogenic uses of these compounds. Brominated flame retardants are produced via direct bromination of organic molecules or via addition of bromine to alkenes; hence, an overview of the production and usage of bromine over the past three decades is covered. Production, application, and environmental occurrence of high production brominated flame retardants including Tetrabromobisphenol A, polybrominated biphenyls, Penta-, Octa-, Deca-brominated diphenyl ether (oxide) formulation and hexabromocyclododecane are discussed.
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            Sperm chromatin structure assay: its clinical use for detecting sperm DNA fragmentation in male infertility and comparisons with other techniques.

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              Ethoxy-, pentoxy- and benzyloxyphenoxazones and homologues: a series of substrates to distinguish between different induced cytochromes P-450.

              The individual members of a homologous series of phenoxazone ethers related to ethoxyresorufin were O-dealkylated, and the parent compound phenoxazone was ring-hydroxylated, each at different rates with hepatic microsomes of untreated rats. A structure-activity relationship (SAR) was plotted, relating the rate of O-dealkylation to the length and type of the ether side-chain. Phenobarbitone (PB), 3-methylcholanthrene (MC), Aroclor 1254 (ARO), isosafrole (ISO) and SKF-525A each induced preferentially the O-dealkylation of different members of the homologous series, resulting in the appearance of 5 different SAR plots, which characterized and differentiated between the 5 different inducers. beta-Napthoflavone (BNF) had a similar effect to MC, whereas pregnenolone 16 alpha-carbonitrile treatment caused no large change in the metabolism of any of the substrates tested. For characterizing the effects of the different inducers it was largely sufficient to compare the O-dealkylations of just 4 of the ethers: methoxy-, ethoxy-, pentoxy- and benzyloxyphenoxazone. Very high degrees of induction were seen. MC and ARO each induced preferentially the O-dealkylation of ethoxyphenoxazone (51- and 61-fold respectively). PB and SKF-525A each induced preferentially the O-dealkylation of pentoxyphenoxazone (283- and 324-fold respectively). ISO induced preferentially the O-dealkylation of benzyloxyphenoxazone (43-fold). For any particular induced type of microsomes the substrate with the fastest metabolism was not necessarily the substrate whose metabolism was induced the most, so that in order to characterize each of the 5 different inducers (PB, MC/BNF, ARO, ISO, SKF) it was necessary to compare both the degrees of induction and the specific activities of the reactions. Experiments with purified cyt. P-450 isozymes showed that ethoxyphenoxazone and pentoxyphenoxazone were highly selective substrates for the major isozymes induced by MC and PB respectively, whilst benzyloxyphenoxazone was a good substrate for both isozymes. Experiments using the organic inhibitors metyrapone and alpha-naphthoflavone and inhibitory antibodies against individual cyt. P-450 isozymes indicated that similar substrate selectivities occurred with the monooxygenase system in the microsomal membrane. It is suggested that the use of some or all of these homologous phenoxazone ethers will provide both a simple routine test for the characterization of several types of inducing agents and a powerful tool for investigating the biochemical basis for cyt. P-450 isozyme substrate selectivity.
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                Author and article information

                Journal
                Toxicol Sci
                Toxicol. Sci
                toxsci
                toxsci
                Toxicological Sciences
                Oxford University Press
                1096-6080
                1096-0929
                June 2012
                2 March 2012
                2 March 2012
                : 127
                : 2
                : 496-507
                Affiliations
                [* ]Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada H3G 1Y6
                []Environmental Health Science & Research Bureau, Health Canada, Ottawa, Ontario, CANADA K1A 0K9
                [§ ]Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada H3G 1Y6
                Author notes
                [1 ]To whom correspondence should be addressed at Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montréal, QC, Canada H3G 1Y6. Fax: +514-398-7120. E-mail: barbara.hales@ 123456mcgill.ca .
                Article
                10.1093/toxsci/kfs098
                3355309
                22387749
                b0280d08-4ca9-4a7b-a02c-e2af70d304e7
                © The Author 2012. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 December 2011
                : 21 February 2012
                Page count
                Pages: 12
                Categories
                Reproductive and Developmental Toxicology

                Pharmacology & Pharmaceutical medicine
                reproductive parameters,mixture,adult male rats,thyroid function,brominated flame retardants,house dust exposure,drug-metabolizing enzymes

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