Szabo David T, Richardson Vicki M, Ross David G, Diliberto Janet J, Kodavanti Prasada R S, Birnbaum Linda S
University of North Carolina Curriculum in Toxicology, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 2009 Jan;107(1):27-39. doi: 10.1093/toxsci/kfn230. Epub 2008 Oct 31.
Previous studies demonstrated that perinatal exposure to polybrominated diphenyl ethers (PBDEs), a major class of brominated flame retardants, may affect thyroid hormone (TH) concentrations by inducing hepatic uridinediphosphate-glucoronosyltransferases (UGTs). This study further examines effects of the commercial penta mixture, DE-71, on genes related to TH metabolism at different developmental time points in male rats. DE-71 is predominately composed of PBDE congeners 47, 99, 100, 153, 154 with low levels of brominated dioxin and dibenzofuran contaminants. Pregnant Long-Evans rats were orally administered 1.7 (low), 10.2 (mid), or 30.6 (high) mg/kg/day of DE-71 in corn oil from gestational day (GD) 6 to postnatal day (PND) 21. Serum and liver were collected from male pups at PND 4, 21, and 60. Total serum thyroxine (T(4)) decreased to 57% (mid) and 51% (high) on PND 4, and 46% (mid) dose and 25% (high) on PND 21. Cyp1a1, Cyp2b1/2, and Cyp3a1 enzyme and mRNA expression, regulated by aryl hydrocarbon receptor, constitutive androstane receptor, and pregnane xenobiotic receptor, respectively, increased in a dose-dependent manner. UGT-T(4) enzymatic activity significantly increased, whereas age and dose-dependent effects were observed for Ugt1a6, 1a7, and 2b mRNA. Sult1b1 mRNA expression increased, whereas that of transthyretin (Ttr) decreased as did both the deiodinase I (D1) enzyme activity and mRNA expression. Hepatic efflux transporters Mdr1 (multidrug resistance), Mrp2 (multidrug resistance-associated protein), and Mrp3 and influx transporter Oatp1a4 mRNA expression increased. In this study the most sensitive responses to PBDEs following DE-71 exposure were CYP2B and D1 activities and Cyb2b1/2, d1, Mdr1, Mrp2, and Mrp3 gene expression. All responses were reversible by PND 60. In conclusion, deiodination, active transport, and sulfation, in addition to glucuronidation, may be involved in disruption of TH homeostasis due to perinatal exposure to DE-71 in male rat offspring.
先前的研究表明，围产期暴露于多溴二苯醚（PBDEs）——一类主要的溴化阻燃剂，可能通过诱导肝脏尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）来影响甲状腺激素（TH）浓度。本研究进一步考察了商用五溴二苯醚混合物DE - 71在雄性大鼠不同发育时间点对TH代谢相关基因的影响。DE - 71主要由PBDE同系物47、99、100、153、154组成，并含有低水平的溴化二噁英和二苯并呋喃污染物。从妊娠第6天（GD）至出生后第21天（PND），给怀孕的Long - Evans大鼠经口灌胃1.7（低）、10.2（中）或30.6（高）mg/kg/天的玉米油溶液形式的DE - 71。在PND 4、21和60收集雄性幼崽的血清和肝脏。血清总甲状腺素（T4）在PND 4时，中剂量组降至57%，高剂量组降至51%；在PND 21时，中剂量组降至46%，高剂量组降至25%。分别受芳烃受体、组成型雄甾烷受体和孕烷异生物质受体调控的Cyp1a1、Cyp2b1/2和Cyp3a1酶及mRNA表达呈剂量依赖性增加。UGT - T(4)酶活性显著增加，而Ugt1a6、1a7和2b mRNA呈现出年龄和剂量依赖性效应。Sult1b1 mRNA表达增加，而甲状腺素运载蛋白（Ttr）的表达下降，脱碘酶I（D1）的酶活性和mRNA表达也下降。肝脏外排转运体多药耐药蛋白1（Mdr1）、多药耐药相关蛋白2（Mrp2）和Mrp3以及摄取转运体有机阴离子转运多肽1a4（Oatp1a4）的mRNA表达增加。在本研究中，DE - 71暴露后对PBDEs最敏感的反应是CYP2B和D1活性以及Cyb2b1/2、d1、Mdr1、Mrp2和Mrp3基因表达。所有反应在PND 60时均可逆转。总之，除了葡萄糖醛酸化外，脱碘、主动转运和硫酸化可能也参与了雄性大鼠后代围产期暴露于DE - 71所导致的TH稳态破坏。
