Metabolomics Approach to Investigate Estrogen Receptor-Dependent and Independent Effects of o,p′-DDT in the Uterus and Brain of Immature Mice

Previous studies have demonstrated
the endocrine disruption of
o,p′-DDT. In this study, we used a 1H NMR based
metabolomics approach to investigate the estrogenic effects of o,p′-DDT
(300 mg/kg) on the uterus and brain after 3 days of oral gavage administration,
and ethynylestradiol (EE, 100 μg/kg) was used as a positive
control. A supervised statistical analysis (PLS-DA) indicated that
o,p′-DDT exerted both estrogenic receptor-(ER)-dependent and
independent effects on the uterus but mainly ER-independent effects
on the brain at metabolome levels, which was verified by coexposing
with the antiestrogenic ICI 182,780. Four changed metabolitesglycine,
choline, fumarate, and phenylalaninewere identified as ER-independent
alterations in the uterus, while more metabolites, including γ-aminobutyrate, N-acetyl aspartate, and some amino acids, were disturbed
based on the ER-independent mechanism in the brain. Together with
biological end points, metabolomics is a promising approach to study
potential estrogenic chemicals.

既往研究已证实邻,对'-滴滴涕（o,p′-DDT）具备内分泌干扰活性。本研究采用基于氢核磁共振（1H NMR）的代谢组学方法，考察经口灌胃给药3天后，300 mg/kg剂量的邻,对'-滴滴涕对子宫与大脑的雌激素样效应，并以100 μg/kg剂量的炔雌醇（EE）作为阳性对照。监督式统计分析（偏最小二乘判别分析，PLS-DA）结果表明，在代谢组层面，邻,对'-滴滴涕对子宫同时存在雌激素受体（ER）依赖性与非依赖性调控作用，而对大脑的影响则主要以ER非依赖性效应为主；该结论通过联合使用抗雌激素药物ICI 182,780进行共暴露实验得到验证。研究共鉴定出4种差异显著的代谢物——甘氨酸、胆碱、延胡索酸与苯丙氨酸，它们均属于子宫中ER非依赖性的改变；而大脑中则有更多代谢物（包括γ-氨基丁酸、N-乙酰天冬氨酸及多种氨基酸）通过ER非依赖性机制发生紊乱。结合生物学终点指标来看，代谢组学方法是研究潜在雌激素类化学物的极具应用前景的手段。