Abstract：
BACKGROUND: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. OBJECTIVES AND METHODS: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. RESULTS: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. CONCLUSION: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.
journal_name
Environ Health Perspectjournal_title
Environmental health perspectivesauthors
Kristensen DM,Skalkam ML,Audouze K,Lesné L,Desdoits-Lethimonier C,Frederiksen H,Brunak S,Skakkebæk NE,Jégou B,Hansen JB,Junker S,Leffers Hdoi
10.1289/ehp.1002635subject
Has Abstractpub_date
2011-04-01 00:00:00pages
534-41issue
4eissn
0091-6765issn
1552-9924journal_volume
119pub_type
杂志文章abstract：:The physiological function of copper(I)-metallothionein is not well understood. The respiratory function of hemocyanin, a copper(I)-containing respiratory protein found in the hemolymph of many invertebrates, has been known a long time. However, the mechanism by which Cu(I) is inserted into the oxygen-binding site of ...
journal_title：Environmental health perspectives
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journal_title：Environmental health perspectives
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更新日期：1978-08-01 00:00:00
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journal_title：Environmental health perspectives
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doi：10.1289/ehp.8982259
更新日期：1989-07-01 00:00:00
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journal_title：Environmental health perspectives
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更新日期：1996-12-01 00:00:00
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journal_title：Environmental health perspectives
pub_type： 杂志文章,评审
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更新日期：1995-11-01 00:00:00
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journal_title：Environmental health perspectives
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更新日期：2017-04-01 00:00:00
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journal_title：Environmental health perspectives
pub_type： 杂志文章
doi：10.1289/ehp.94102s847
更新日期：1994-11-01 00:00:00
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journal_title：Environmental health perspectives
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更新日期：1994-10-01 00:00:00
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更新日期：2016-05-01 00:00:00
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更新日期：2001-01-01 00:00:00
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journal_title：Environmental health perspectives
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更新日期：1998-10-01 00:00:00
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journal_title：Environmental health perspectives
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更新日期：1991-01-01 00:00:00
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更新日期：1994-10-01 00:00:00
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journal_title：Environmental health perspectives
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journal_title：Environmental health perspectives
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更新日期：1995-03-01 00:00:00
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journal_title：Environmental health perspectives
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更新日期：1996-05-01 00:00:00
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更新日期：2007-11-01 00:00:00
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更新日期：2009-01-01 00:00:00
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更新日期：2009-12-01 00:00:00
