Two important ingredients of personal care products, namely polycyclic musk fragrances and UV filters, can be found in the environment and in humans. In previous studies, several compounds of both classes have been tested for their interaction with the estrogen receptor. Two polycyclic musk fragrances, namely AHTN and HHCB, turned out to be anti-estrogenic both in vitro and in vivo in a transgenic zebrafish assay. Several UV filters have been shown to exert estrogenic effects in vitro and in some in vivo studies. Here, we assessed the interaction of five polycyclic musk compounds and seven UV filters with the estrogen receptor (ER), androgen receptor (AR), and progesterone (PR) receptor, using sensitive and specific reporter gene cell lines. Four polycyclic musks (AHTN, HHCB, AETT, and AHMI) were found to be antagonists toward the ERbeta, AR and PR. The UV filters that showed estrogenic effects (benzophenone-3, Bp-3; 3-benzylidene camphor, 3-BC; homosalate, HMS; and 4-methylbenzylidene camphor, 4-MBC) were found to be antagonists toward the AR and PR. The ERalpha agonistic UV filter octyl-dimethyl-p-aminobenzoic acid (OD-PABA) did not show activity toward the AR and PR. Octyl methoxy cinnamate (OMC) showed weak ERalpha agonism, but potent PR antagonism. Butyl methoxydibenzoylmethane (B-MDM) only showed weak ERalpha agonism and weak AR antagonism. Most effects were observed at relatively high concentrations (above 1 muM); however, the anti-progestagenic effects of the polycyclic musks AHMI and AHTN were detected at concentrations as low as 0.01 muM. The activity of anti-progestagenic xenobiotics at low concentrations indicates the need to undertake more research to find out about the potential endocrine disrupting effects of these compounds in vivo.
In vitro assays and computer models are promising alternatives for in vivo animal testing, but the power of these alternative methods to predict in vivo risk is still very limited. One step forward is to make the outcome of in vitro assays (such as median effect concentrations (EC50 values)) independent of assay conditions such as protein content. Here we show that measured free concentrations of chemicals in the in vitro assay medium result in system-independent EC50 values. We introduce a very simple method to measure free concentrations in miniature test systems using negligible depletion solid-phase microextraction. The generated data are much more suitable for extrapolation to in vivo, provide unbiased input for computational methods (for example, quantitative structure-activity relationships), and can shed an entirely different light on the activity of environmental contaminants.
In the past decade the list of chemicals in the environment that are able to mimic the natural hormone estrogen, thereby disrupting endocrine function, has grown rapidly. These chemicals are able to bind to estrogen receptors (ERs) and influence estrogen signalling pathways, although several of them have structures that differ substantially from the endogenous hormone 17beta-estradiol. In this study, six extensively used ultraviolet (UV) filters were assessed for transcriptional activation of estrogen receptors. Because of their high lipophilicity, these UV filters tend to bioaccumulate in the environment. They have been found in surface waters, fish, and in human milk fat. Using a sensitive in vitro reporter gene assay, we found that all six compounds induce estrogenic activity towards ERalpha, while four out of six compounds induced transcriptional activity of ERbeta. Zebrafish, in which an estrogen responsive luciferase reporter gene has been stably introduced, were used for in vivo testing. In this transgenic zebrafish assay none of the compounds showed estrogenic activity. Our findings suggest that one should be aware of over-interpretation when predicting in vivo effects from weak in vitro data. However, it can not be ruled out that these UV filters have long-term effects in the environment.
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