title: Rodent thyroid, liver, and fetal testis toxicity of the monoester metabolite of bis-(2-ethylhexyl) tetrabromophthalate (tbph), a novel brominated flame retardant present in indoor dust.
abstract: BACKGROUND
  Bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a replacement for polybrominated diphenyl ethers (PBDEs) in commercial flame retardant mixtures such as Firemaster 550. It is also used in a commercial mixture called DP 45. Mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) is a potentially toxic metabolite.
  
  
  OBJECTIVE
  We used in vitro and rodent in vivo models to evaluate human exposure and the potential metabolism and toxicity of TBPH.
  
  
  METHODS
  Dust collected from homes, offices, and cars was measured for TBPH by gas chromatography followed by mass spectrometry. Pregnant rats were gavaged with TBMEHP (200 or 500 mg/kg) or corn oil on gestational days 18 and 19, and dams and fetuses were evaluated histologically for toxicity. We also assessed TBMEHP for deiodinase inhibition using rat liver microsomes and for peroxisome proliferator-activated receptor (PPAR) α and γ activation using murine FAO cells and NIH 3T3 L1 cells.
  
  
  RESULTS
  TBPH concentrations in dust from office buildings (median, 410 ng/g) were higher than in main living areas in homes (median, 150 ng/g). TBPH was metabolized by purified porcine esterases to TBMEHP. Two days of TBMEHP exposure in the rat produced maternal hypothyroidism with markedly decreased serum T3 (3,3´,5-triiodo-l-thyronine), maternal hepatotoxicity, and increased multinucleated germ cells (MNGs) in fetal testes without antiandrogenic effects. In vitro, TBMEHP inhibited deiodinase activity, induced adipocyte differentiation in NIH 3T3 L1 cells, and activated PPARα- and PPARγ-mediated gene transcription in NIH 3T3 L1 cells and FAO cells, respectively.
  
  
  CONCLUSIONS
  TBPH a) is present in dust from indoor environments (implying human exposure) and b) can be metabolized by porcine esterases to TBMEHP, which c) elicited maternal thyrotoxic and hepatotoxic effects and d) induced MNGs in the fetal testes in a rat model. In mouse NIH 3T3 L1 preadipocyte cells, TBMEHP inhibited rat hepatic microsome deiodinase activity and was an agonist for PPARs in murine FAO and NIH 3T3 L1 cells.
authors.affiliation: Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Springer
authors.forename: Edward
authors.initials: E
authors.lastname: Dere
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hall
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: McDonnell
authors.forename: Simon C
authors.initials: SC
authors.lastname: Roberts
authors.forename: Craig M
authors.initials: CM
authors.lastname: Butt
authors.forename: Heather M
authors.initials: HM
authors.lastname: Stapleton
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Watkins
authors.forename: Michael D
authors.initials: MD
authors.lastname: McClean
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Webster
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Schlezinger
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
mesh_terms: D000393:Air Pollutants / Q000032:analysis / Q000097:blood / Q000378:metabolism* / Q000633:toxicity*; D016902:Air Pollution, Indoor / Q000009:adverse effects* / Q000032:analysis; D000818:Animals; D001336:Automobiles; D001900:Boston; D001970:Bromobenzoates / Q000032:analysis / Q000097:blood / Q000378:metabolism* / Q000633:toxicity*; D004391:Dust / Q000032:analysis; D004781:Environmental Exposure; D004784:Environmental Monitoring; D004950:Esterases / Q000378:metabolism; D005260:Female; D005333:Fetus; D005411:Flame Retardants / Q000032:analysis / Q000378:metabolism / Q000633:toxicity; D055768:Halogenated Diphenyl Ethers / Q000032:analysis / Q000097:blood / Q000378:metabolism* / Q000633:toxicity*; D006798:Housing; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010795:Phthalic Acids; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D013552:Swine; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution; D017132:Workplace
chemical_list: D000393:Air Pollutants; D001970:Bromobenzoates; D004391:Dust; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D010795:Phthalic Acids; C576262:bis(2-ethylhexyl) 2,3,4,5-tetrabromophthalate; D004950:Esterases