Perinatal exposure to BDE-99 causes decreased protein levels of cyclin D1 via GSK3β activation and increased ROS production in rat pup livers.
We here examined the potential liver toxicity in rat pups from dams exposed during the gestational and lactation periods to 2,2',4,4',5-pentabromodiphenyl ether (BDE-99). Dams were exposed to 0, 1, and 2mg/kg/day of BDE-99 from gestation day 6 to postnatal day 21. When the pups were weaning, the liver from 1 pup of each litter was excised to evaluate oxidative stress markers and the messenger RNA (mRNA) expression of multiple cytochrome P450 (CYP) isoforms. To determine whether thyroid hormone (TH) was disrupted, the protein and mRNA expressions of several TH receptor (TR) isoforms, as well as the protein levels of cyclin D1 and the phosphorylated protein kinases Akt and glycogen synthase kinase 3 beta (GSK3β), were evaluated. Perinatal exposure to BDE-99 produced decreased levels of cyclin D1 in rat pup livers. A decrease in the active form of Akt and an increase in the active form of GSK3β were observed. The decreased Akt pathway may be due to a potential disruption of the nongenomic actions of TH by BDE-99 and its metabolites. This possible TH disruption was noted as a decrease in TR isoforms expression. By contrast, we observed an upregulation of CYP2B1 gene expression, which is correlated with an increase in reactive oxygen species production. This outcome indicates activation of the nuclear constitutive androstane receptor, which could induce the expression of other enzymes capable of metabolizing TH. The present findings support the hypothesis that perinatal exposure to PBDEs, at levels found in humans, may have serious implications for metabolic processes in rat pup livers.
* Laboratory of Toxicology and Environmental Health and.
Jordi
J
Blanco
Miquel
M
Mulero
Jose L
JL
Domingo
Domènec J
DJ
Sanchez
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D019938:Cyclin D1 / Q000096:biosynthesis*; D005260:Female; D005411:Flame Retardants / Q000633:toxicity*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
C477694:2,2',4,4',5-brominated diphenyl ether; D000975:Antioxidants; D015415:Biomarkers; C530106:Ccnd1 protein, rat; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
Akt; BDE-99; CYP enzyme system; GSK3β; cyclin D1.; reactive oxygen species; thyroid hormone receptors