Wadzinski Thomas L, Geromini Katherine, McKinley Brewer Judy, Bansal Ruby, Abdelouahab Nadia, Langlois Marie-France, Takser Larissa, Zoeller R Thomas
Department of Biology (T.L.W., K.G., J.M.B., R.B., R.T.Z.), University of Massachusetts Amherst, Amherst, Massachusetts 01003; Department of Pediatrics (T.L.W.), Baystate Medical Center, Springfield, Massachusetts 01199; and Department of Pediatrics (N.A., L.T.), Faculty of Medicine, and Department of Medicine (M.-F.L.), Endocrinology Service, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Qéubec, Canada J1H SN4.
J Clin Endocrinol Metab. 2014 Dec;99(12):E2735-43. doi: 10.1210/jc.2014-2629.
Thyroid hormone (TH) is essential for normal development; therefore, disruption of TH action by a number of industrial chemicals is critical to identify. Several chemicals including polychlorinated biphenyls are metabolized by the dioxin-inducible enzyme CYP1A1; some of their metabolites can interact with the TH receptor. In animals, this mechanism is reflected by a strong correlation between the expression of CYP1A1 mRNA and TH-regulated mRNAs. If this mechanism occurs in humans, we expect that CYP1A1 expression will be positively correlated with the expression of genes regulated by TH.
The objective of the study was to test the hypothesis that CYP1A1 mRNA expression is correlated with TH-regulated mRNAs in human placenta.
One hundred sixty-four placental samples from pregnancies with no thyroid disease were obtained from the GESTE study (Sherbrooke, Québec, Canada). Maternal and cord blood TH levels were measured at birth. The mRNA levels of CYP1A1 and placental TH receptor targets [placental lactogen (PL) and GH-V] were quantitated by quantitative PCR.
CYP1A1 mRNA abundance varied 5-fold across 132 placental samples that had detectable CYP1A1 mRNA. CYP1A1 mRNA was positively correlated with PL (r = 0.64; P < .0001) and GH-V (P < .0001, r = 0.62) mRNA. PL and GH-V mRNA were correlated with each other (r = 0.95; P < .0001), suggesting a common activator. The mRNAs not regulated by TH were not correlated with CYP1A1 expression.
CYP1A1 mRNA expression is strongly associated with the expression of TH-regulated target gene mRNAs in human placenta, consistent with the endocrine-disrupting action of metabolites produced by CYP1A1.
甲状腺激素（TH）对正常发育至关重要；因此，识别多种工业化学品对TH作用的干扰至关重要。包括多氯联苯在内的几种化学品可被二噁英诱导酶CYP1A1代谢；它们的一些代谢产物可与TH受体相互作用。在动物中，这种机制表现为CYP1A1 mRNA表达与TH调节的mRNA之间存在强相关性。如果这种机制在人类中也存在，我们预计CYP1A1表达将与受TH调节的基因表达呈正相关。
本研究的目的是检验CYP1A1 mRNA表达与人类胎盘TH调节的mRNA相关这一假设。
从GESTE研究（加拿大魁北克省舍布鲁克）中获取了164份无甲状腺疾病孕妇的胎盘样本。出生时测量母体和脐带血中的TH水平。通过定量PCR对CYP1A1和胎盘TH受体靶点[胎盘催乳素（PL）和生长激素变异体（GH-V）]的mRNA水平进行定量。
在132份可检测到CYP1A1 mRNA的胎盘样本中，CYP1A1 mRNA丰度变化了5倍。CYP1A1 mRNA与PL（r = 0.64；P < 0.0001）和GH-V（P < 0.0001，r = 0.62）mRNA呈正相关。PL和GH-V mRNA相互相关（r = 0.95；P < 0.0001），提示存在共同激活因子。不受TH调节的mRNA与CYP1A1表达不相关。
CYP1A1 mRNA表达与人类胎盘TH调节的靶基因mRNA表达密切相关，这与CYP1A1产生的代谢产物的内分泌干扰作用一致。
