Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

Abstract

BackgroundProstaglandins (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 MethodsUsing 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.ResultsWe 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.ConclusionOur 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.

Ubiquitous presence of paracetamol in human urine: sources and implications

“…In the same study, the authors reported a reduced production of PGD2 and testosterone in ex vivo fetal rat testes (Kristensen et al 2010). A study carried out by Kristensen et al (2011) that many presumed endocrine-disrupting chemicals (EDCs) dose dependently inhibited PGD2 synthesis in mouse Sertoli cell lines. The observed effect was comparable within the tested analgesics, which included NA4AP, aspirin, and ibuprofen, and was even higher than the measured effect of other known EDCs such as n-butylparaben and bisphenol A.…”

“…Therefore, the authors concluded that pharmaceutical PG inhibitors such as NA4AP, aspirin, and ibuprofen may act as endocrine disruptors. The authors were also able to pinpoint the suppression of PG synthesis to the inhibition of cyclooxygenase (COX) enzymes (Kristensen et al 2011). It is thought that NA4AP acts as an inhibitor of COX enzymes, although the precise mechanism of action is still unclear (Hinz et al 2007).…”

The influence of antenatal exposure to phthalates on subsequent female reproductive development in adolescence: a pilot study

“…Samples from a thawed aliquot from both time points from 123 individuals were pooled for analysis of phthalate metabolites to provide an approximation of antenatal phthalate exposure across gestation. As phthalates are non-persistent chemicals, exposure can vary from day to day, but individuals tend to follow their trajectories (Frederiksen et al 2011). For analysis, the pooled aliquot (400 ml) was couriered frozen to Copenhagen, Denmark.…”

“…There are several known mechanisms of action for these effects on the male rat, such as the inhibition of testosterone synthesis (Auharek et al 2010, Christiansen et al 2010, MacLeod et al 2010, Boberg et al 2011, inhibition of E 2 synthesis in granulosa cells (Reinsberg et al 2009) as well as inhibition of aromatase activity (van Meeuwen et al 2008), prostaglandin synthesis (Kristensen et al 2011) and possibly effects via inhibition of the thyroid axis (Meeker & Ferguson 2011). This makes the interpretation of in vivo effects in humans very complex.…”

Sex Differences in the Developmental Programming of Adult Disease

“…The alteration of synthesis of prostaglandins from arachadonic acid through the COX enzyme has been shown disrupt endocrine processes. Several phthalates that are similar to pharmaceutical COX inhibitors, were found to disrupt the levels of prostaglandin synthesis (Kristensen et al, 2011). Chronic inhibition of COX activity is known to have deleterious effects on renal and cardiovascular function, resulting in mild to moderate hypertension and even renal failure.…”