Low concentrations of o,p'-DDT inhibit gene expression and prostaglandin synthesis by estrogen receptor-independent mechanism in rat ovarian cells.
Low concentrations of o,p'-DDT inhibit gene expression and prostaglandin synthesis by estrogen receptor-independent mechanism in rat ovarian cells.
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DOI：
10.1371/journal.pone.0049916
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Liu J;Zhao M;Zhuang S;Yang Y;Yang Y;Liu W
o,p ' -DDT是一种臭名昭著的雌激素，也是一种无处不在的持久性污染物。生物监测研究表明，妇女已在血液和其他组织中暴露于0.3-500 ng/g （8.46×10−10 M−1.41×10−6 M）范围内的o，p ' -滴滴涕。然而，非常有限的研究调查了o，p ' -滴滴涕在等于或低于目前人体暴露水平时的生物效应和机制。在这项研究中，我们利用大鼠卵巢颗粒细胞的原代培养，确定了极低剂量的o，p ' -DDT（10−12−10−8 M）抑制卵巢基因的表达和前列腺素E2 （PGE2）的产生。体内实验一致证明0.5-1 mg/kg的o，p ' -DDT能抑制大鼠卵巢基因表达和PGE2水平。受体抑制剂研究的惊人结果表明，这些抑制作用独立于经典雌激素受体（er）或G蛋白偶联受体30 （GPR30）发挥作用。相反，o,p ' -DDT通过抑制蛋白激酶A （PKA）的激活而不是蛋白激酶C （PKC）来改变基因表达或激素作用。我们进一步发现o，p ' -DDT直接干扰PKA催化亚基。我们的新发现支持了这样的假设，即暴露于低浓度的o，p ' -滴滴涕会通过受体结合以外的信号介质改变基因表达和激素合成，并暗示目前在人群中观察到的o，p ' -滴滴涕暴露水平可能对女性生殖构成健康风险。
o,p’-DDT is an infamous xenoestrogen as well as a ubiquitous and persistent pollutant. Biomonitoring studies show that women have been internally exposed to o,p’-DDT at range of 0.3–500 ng/g (8.46×10−10 M−1.41×10−6 M) in blood and other tissues. However, very limited studies have investigated the biological effects and mechanism(s) of o,p’-DDT at levels equal to or lower than current exposure levels in human. In this study, using primary cultures of rat ovarian granulosa cells, we determined that very low doses of o,p’-DDT (10−12−10−8 M) suppressed the expression of ovarian genes and production of prostaglandin E2 (PGE2). In vivo experiments consistently demonstrated that o,p’-DDT at 0.5–1 mg/kg inhibited the gene expression and PGE2 levels in rat ovary. The surprising results from the receptor inhibitors studies showed that these inhibitory effects were exerted independently of either classical estrogen receptors (ERs) or G protein-coupled receptor 30 (GPR30). Instead, o,p’-DDT altered gene expression or hormone action via inhibiting the activation of protein kinase A (PKA), rather than protein kinase C (PKC). We further revealed that o,p’-DDT directly interfered with the PKA catalytic subunit. Our novel findings support the hypothesis that exposure to low concentrations of o,p’-DDT alters gene expression and hormone synthesis through signaling mediators beyond receptor binding, and imply that the current exposure levels of o,p’-DDT observed in the population likely poses a health risk to female reproduction.
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影响因子：
10.4
作者：
Frigo, Daniel E;Burow, Matthew E;Mitchell, Kamron A;Chiang, Tung-Chin;McLachlan, John A
通讯作者：
McLachlan, John A
影响因子：
168.9
作者：
Cohn, BA;Cirillo, PM;Siiteri, PK
通讯作者：
Siiteri, PK
影响因子：
4.8
作者：
GELLERT, RJ;SWERDLOF.RS;HEINRICH.WL
通讯作者：
HEINRICH.WL
影响因子：
--
作者：
Jo, Misung;Curry, Thomas E., Jr.
通讯作者：
Curry, Thomas E., Jr.
影响因子：
6.1
作者：
Axmon, A;Thulstrup, AM;Hagmar, L
通讯作者：
Hagmar, L