Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Environ Health Perspect. 2011 Apr;119(4):534-41. doi: 10.1289/ehp.1002635. Epub 2010 Nov 16.
Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine-disrupting compounds (EDCs) share a high degree of structural similarity with mild analgesics.
Using cell-based transfection and transduction experiments, mass spectrometry, and organotypic assays together with molecular modeling, we investigated whether inhibition of the PG pathway by known EDCs could be a novel point of endocrine disruption.
We found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis, and this reduction was correlated with a reduced testosterone production. The inhibition of PG synthesis occurred without involvement of canonical PG receptors or the peroxisome proliferator-activated receptors (PPARs), which have previously been described as targets of EDCs. Instead, our results suggest that the compounds may bind directly into the active site of the cyclooxygenase (COX) enzymes, thereby obstructing the conversion of arachidonic acid to PG precursors without interfering with the expression of the COX enzymes. A common feature of the PG inhibitory EDCs is the presence of aromatic groups that may stabilize binding in the hydrophobic active site of the COX enzymes.
Our findings suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades.
前列腺素（PGs）在成年机体的发育和维持内稳态方面发挥着关键作用。尽管这些作用非常重要，但PG 途径是否是内分泌干扰的靶点仍不清楚。然而，几种已知的内分泌干扰化合物（EDCs）与轻度镇痛药具有高度的结构相似性。
我们使用基于细胞的转染和转导实验、质谱分析以及器官样培养和分子建模，研究了已知 EDC 通过抑制 PG 途径是否可能成为一种新的内分泌干扰点。
我们发现，许多已知的 EDC 在小鼠支持细胞系和人原代肥大细胞中抑制 PG 途径。EDC 还减少了离体大鼠睾丸中的 PG 合成，这种减少与睾酮产生减少相关。PG 合成的抑制没有涉及经典的 PG 受体或过氧化物酶体增殖物激活受体（PPARs），这些受体先前已被描述为 EDC 的靶标。相反，我们的结果表明，这些化合物可能直接结合到环氧化酶（COX）酶的活性部位，从而阻止花生四烯酸转化为 PG 前体，而不干扰 COX 酶的表达。PG 抑制性 EDC 的一个共同特征是存在芳香基团，这些基团可能稳定结合在 COX 酶的疏水性活性部位。
我们的研究结果表明，EDCs 通过抑制 PG 途径发挥了一种迄今为止未知的作用机制，并提出了新的途径来研究 EDC 对生殖和免疫紊乱的影响，这些影响在最近几十年变得越来越普遍。
