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产前和哺乳期暴露于重组多氯联苯混合物的大鼠子代肝和脑细胞色素 P450 的反应性。

Responsiveness of hepatic and cerebral cytochrome P450 in rat offspring prenatally and lactationally exposed to a reconstituted PCB mixture.

机构信息

Dipartimento di Scienze dell'Ambiente e del Territorio, Università di Milano Bicocca, P.zza della Scienza 1, 20126 Milano, Italy.

出版信息

Environ Toxicol. 2014 Aug;29(8):856-66. doi: 10.1002/tox.21812. Epub 2012 Sep 15.

DOI:10.1002/tox.21812
PMID:22987612
Abstract

Perinatal polychlorinated biphenyl (PCB) exposures still remain a serious health concern because offspring receive PCB burden from mother during vulnerable processes of development. Since cytochrome P450 (CYP) represents a toxicological endpoint, in the present study, representing an extended investigation of a previous multitasked one, we explored the long-term responsiveness of CYP1A and CYP2B isoforms by Western blot analysis in liver and whole brain of lactating (PN12), weaning (PN21), and adult offspring (PN60) rats prenatally and lactationally exposed to a reconstituted PCB mixture (RM) of noncoplanar PCB138, 153, 180, and coplanar PCB126 congeners. We chose highly chlorinated PCBs instead of lower chlorinated one, because their recalcitrance to biotransformation makes easy their accumulation/persistence in tissues and breast milk. Dioxin-like congener PCB126 binding aryl hydrocarbon receptor (AHR) is responsible of many toxic effects. Pregnant Sprague-Dawley dams with high affinity AHR received subcutaneous injection of RM (10 mg/kg body weight) daily during gestation (days 15-19) and twice a week during breast-feeding. The results evidenced a transfer of PCBs to neonates through milk and a significant responsiveness of hepatic CYP in both mothers and offspring. In liver of exposed progeny, CYP isoforms exhibited a significant increment at PN12 (70% over control) and at PN21 (270% over control). Contrary to dams, in adult PCB offspring CYP levels showed a decline up to values similar to those of control. This transient developmental responsiveness of CYP isoforms in offspring liver reflects roughly the time course of hepatic PCB levels previously reported. Even if congeners were detected in brain, we failed in evidencing a responsiveness of CYP isoforms probably because of region-specific CYP expression in this organ. In conclusion, induction of offspring hepatic CYP is index of liver PCB burden, and despite the insensitivity of whole brain CYP we cannot exclude brain vulnerability toward PCB. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 856-866, 2014.

摘要

围产期多氯联苯(PCB)暴露仍然是一个严重的健康问题,因为后代在发育过程中会从母亲那里获得 PCB 负担。由于细胞色素 P450(CYP)代表毒理学终点,因此在本研究中,我们通过 Western blot 分析探索了 CYP1A 和 CYP2B 同工型的长期反应性,该研究代表了之前多任务研究的扩展研究,在产前和哺乳期暴露于非共平面 PCB138、153、180 和共平面 PCB126 同系物的重组 PCB 混合物(RM)的哺乳期(PN12)、断奶期(PN21)和成年后代(PN60)大鼠的肝和全脑中。我们选择高氯化 PCB 而不是低氯化 PCB,因为它们不易生物转化,容易在组织和母乳中积累/持续存在。二恶英样同系物 PCB126 结合芳香烃受体(AHR)负责许多毒性作用。具有高亲和力 AHR 的怀孕 Sprague-Dawley 母鼠在妊娠(第 15-19 天)期间每天接受 RM(10mg/kg 体重)皮下注射,在哺乳期每周接受两次注射。结果表明,PCBs 通过乳汁转移到新生儿体内,并且暴露后代的肝 CYP 具有明显的反应性。在暴露后代的肝脏中,CYP 同工型在 PN12 时表现出显著增加(比对照增加 70%),在 PN21 时增加 270%(比对照增加)。与母体相反,在成年 PCB 后代中,CYP 水平下降到与对照相似的值。这种后代肝脏中 CYP 同工型的短暂发育反应性大致反映了先前报道的肝 PCB 水平的时间过程。尽管在大脑中检测到了同系物,但我们未能证明 CYP 同工型的反应性,这可能是由于该器官中特定于区域的 CYP 表达。总之,诱导后代肝 CYP 是肝 PCB 负荷的指标,尽管全脑 CYP 不敏感,但我们不能排除 PCB 对大脑的易感性。2012 年 Wiley 期刊,环境毒理学 29:856-866,2014 年。

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