Publication details
Potential endocrine disrupting effects of clofibric acid
| Authors | |
|---|---|
| Year of publication | 2005 |
| Type | Article in Proceedings |
| Conference | ECOTOX 2005 : : "Advances and trends in ecotoxicology" : book of abstracts |
| MU Faculty or unit | |
| Citation | |
| Field | Environment influence on health |
| Keywords | clofibric acid; endocrine disruption |
| Description | Pharmaceutical drugs are produced and used by human populations in quantities that exceed hundreds of metric tones annually and most of these drugs or their metabolites are excreted or discarded into surface water via sewage effluents. Clofibric acid (CA), the active substance of lipid lowering drugs (e.g. clofibrate, etofyllin clofibrate, etofibrate) which are used in human medical care for a reduction of high amounts of cholesterol and triglyceride in blood, is widespread in the aquatic environment. CA is classified as a peroxisomal proliferator increasing the number and the size of cellular peroxisomes not only in the liver, but also in many other tissues of susceptible species, mainly rodents. Recently, CA was identified as a specific ligand for the peroxisome proliferator activated receptor alpha (PPARalpha). After its activation, PPARalpha binds to specific responsive elements of the target genes, mainly in genes of enzymes involved in fatty metabolism. Thus, CA can have effects on the gene expression of target or non-target species. Since a few years a link between lipid lowering drugs and estrogens is discussed. It is suggested that CA may prolong or enhance the hormonal action of endogenous estradiol, particularly in lipid-rich tissues. For the evaluation of potential endocrine disrupting effects of CA, we used a combination of cellular and molecular test systems. The test systems include an MCF-7 cell proliferation test (E-Screen) and gene expression analysis by quantitative RT-PCR in primary rainbow trout hepatocytes. We studied effects of not only CA alone, but also in the mixture with one natural estrogen, 17-beta-estradiol (E2). In the MCF-7 proliferation assay, a CA-dependent proliferative effect was found. This proliferative effect was blocked by addition of the ER-inhibitor ICI 182,780. In primary rainbow trout hepatocytes, CA was able to induce the time and concentration dependent expression of the vitellogenin gene in both sexes. Further investigations in this regards were hampered by the fact that the results of hepatocytes of the vitellogenic female fish (female at the beginning of vitellogenesis) were not replicated in hepatocytes from a non-vitellogenic female fish. Co-exposure to E2 and CA led to the reduction of the VTG response of E2 alone. The same effect was observed after pretreatment of E2 and subsequent exposure to CA. Future independent investigations focusing on the confirmation and the mechanisms of CA-dependent estrogen effects are necessary. Potential alternations in mRNA abundance of several genes involved in fatty acid transport and metabolism, microsomal xenobiotic metabolism and peroxisome metabolism, steroid metabolism, oxidative stress, cell proliferation, apoptosis and cell death were investigated in primary rainbow trout hepatocytes for the detailed estimation of mechanisms of CA-dependent toxic and endocrine disrupting effects. Interestingly, no induction of apolipoprotein CII (apoCII) and fatty binding protein (FABP) were detected upon exposure to CA alone, although apoCII is an activator of lipoprotein lipase that is one key enzyme in fatty acid catabolism and one target of fibrates to which clofibric acid belongs. In accord with results in literature, our results indicate that clofibric acid could have estrogenic effect. However, these results have to be repeated in other independent experiments. Future experiments should be focused on the clarification of mechanistic effects as well. |