Pharmacokinetics of Bisphenol A in neonatal and adult CD-1 mice: Inter-species comparisons with Sprague-Dawley rats and rhesus monkeys
Pharmacokinetics of Bisphenol A in neonatal and adult CD-1 mice: Inter-species comparisons with Sprague-Dawley rats and rhesus monkeys
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DOI：
10.1016/j.toxlet.2011.09.020
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发表时间：
2011-12-15
影响因子：
3.5
通讯作者：
Fisher, Jeffrey W.
中科院分区：
文献类型：
--
作者：
Doerge, Daniel R.;Twaddle, Nathan C.;Fisher, Jeffrey W.
双酚A（BPA）是一种重要的工业化学品，用于制造聚碳酸酯塑料产品和环氧树脂食品罐内衬。>90%的6-60岁的美国人尿液中存在BPA代谢物，这表明普遍和频繁的暴露水平大大低于1 μ g/kg bw/d。本研究使用LC/MS/MS通过经口和皮下（SC）注射途径测定成年和新生CD-1小鼠中非结合（活性）和结合（非活性）BPA的血清药代动力学。使用氘代BPA以避免背景污染问题。出生后的年龄和测量的内部暴露（C-max）口服给药后未结合BPA之间观察到显着的负相关关系。II相结合，时间-浓度曲线下面积（AUC）和未结合BPA的消除半衰期也与年龄呈负相关。在出生后第3天（PND）的小鼠中，发育不全的II期代谢、快速吸收和缓慢消除动力学的组合导致口服和SC途径的未结合BPA的内部暴露量相等;然而，PND 10和更年长小鼠的成熟代谢能力导致了较大且显著的途径效应。CD-1小鼠和Sprague-Dawley大鼠经口给药的未结合BPA内部暴露指标从PND 3到成年期的显著逆年龄相关发育特征非常相似：然而，新生恒河猴的发育特征完全不同，其中观察到微小的不显著的年龄相关差异。这些结果表明，在啮齿动物模型中观察到的BPA不良反应（归因于新生儿发育的离散时间段内的暴露），基于内部剂量测定法，对于可比的新生灵长类动物给药，可能性较小。另一方面，在研究的所有物种（包括人类）的所有成年人中，低口服剂量的BPA对非结合形式产生了类似的小的内部暴露，反映了系统前II期代谢的主导作用。出版社：Elsevier爱尔兰Ltd.
Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA metabolites in urine of >90% of Americans aged 6-60 suggests ubiquitous and frequent exposure at levels largely below 1 mu g/kg bw/d. The current study used LC/MS/MS to measure serum pharmacokinetics of unconjugated (active) and conjugated (inactive) BPA in adult and neonatal CD-1 mice by oral and subcutaneous (SC) injection routes. Deuterated BPA was used to avoid issues of background contamination. Significant inverse relationships were observed between postnatal age and measures of internal exposures (C-max) to unconjugated BPA after oral administration. Phase II conjugation, area under the time-concentration curve (AUC), and elimination half-time of unconjugated BPA were also inversely related to age. In postnatal day (PND) 3 mice, the combination of under-developed Phase II metabolism, rapid absorption, and slow elimination kinetics led to equivalent internal exposures for unconjugated BPA from oral and SC routes; however, maturing metabolic capabilities in PND 10 and older mice, led to large and significant route effects. The significant inverse age-related developmental profiles from PND 3 through adulthood for unconjugated BPA internal exposure metrics from oral administration to CD-1 mice and Sprague-Dawley rats were remarkably similar: however, the developmental profile was quite different for neonatal rhesus monkeys in which small insignificant age-related differences were observed. These results suggest that an adverse effect from BPA observed in rodent models, attributable to exposure during a discrete time period of neonatal development, would be less likely for comparable neonatal primate dosing based on internal dosimetry. On the other hand in all adults of all species studied, including humans, a low oral dose of BPA produced similarly small internal exposures for the unconjugated form, reflecting the dominant effect of presystemic Phase II metabolism. Published by Elsevier Ireland Ltd.