Nitromusk and Polycyclic Musk Compounds as Long-Term Inhibitors of Cellular Xenobiotic Defense Systems Mediated by Multidrug Transporters

Abstract

Synthetic musk compounds, widely used as fragrances in consumer products, have been detected in human tissue and, surprisingly, in aquatic organisms such as fish and mollusks. Although their persistence and potential to bioaccumulate are of concern, the toxicity and environmental risks of these chemicals are generally regarded as low. Here, however, we show that nitromusks and polycyclic musks inhibit the activity of multidrug efflux transporters responsible for multixenobiotic resistance (MXR) in gills of the marine mussel Mytilus californianus. The IC10 (concentration that inhibits 10%) values for the different classes of musks were in the range of 0.09–0.39 μM, and IC50 values were 0.74–2.56 μM. The immediate consequence of inhibition of efflux transporters is that normally excluded xenobiotics will now be able to enter the cell. Remarkably, the inhibitory effects of a brief 2-hr exposure to musks were only partially reversed after a 24- to 48-hr recovery period in clean seawater. This unexpected consequence of synthetic musks—a long-term loss of efflux transport activity—will result in continued accumulation of normally excluded toxicants even after direct exposure to the musk has ended. These findings also point to the need to determine whether other environmental chemicals have similar long-term effects on these transporters. The results are relevant to human health because they raise the possibility that exposure to common xenobiotics and pharmaceuticals could cause similar long-term inhibition of these transporters and lead to increased exposure to normally excluded toxicants.

Toxicity of Synthetic Musks to Early Life Stages of the Freshwater Mussel Lampsilis cardium

“…Recently, HHCB and AHTN were found to compromise the multixenobiotic defense system in marine mussels, suggesting they may play a role as chemosensitizers that enable toxic multixenobiotic resistance substrates to accumulate in cells (Luckenbach and Epel 2005;Luckenbach et al 2004). Given these recent mechanistic studies, endpoints that relate more directly to the mode of action of musks should be considered.…”

“…Recently, Luckenbach et al (2004) demonstrated that four polycyclic musks, including AHTN and HHCB, compromised multixenobiotic defense systems (mxr transporters) in the marine mussel Mytilus californianus in the μM range (200-2000 μg/L). A long-term loss of efflux transporter activity can result in continued accumulation of normally excluded toxicants even after direct exposure to the musk has ended, and thus, may increase an organisms susceptibility to other toxicants (Luckenbach and Epel 2005). …”

Screening level ecological risk assessment for synthetic musks in surface water of Lake Taihu, China

“…The inhibition of larval development in the calanoid copepod (Acartia tonsa) was associated with exposure to HHCB and AHTN (Wollenberger et al 2003). Multi-xenobiotic resistance in the gills of the marine mussel was inhibited by SM (Mytilus californianus) (Luckenbach and Epel 2005). Moreover, HHCB and AHTN have been shown to present both estrogenic and anti-estrogenic activity during in vitro and in vivo experiments using zebrafish (Danio rerio) (Schreurs et al 2004).…”

Dangerous cosmetics - criteria for classification, labelling and packaging (EC 1272/2008) applied to personal care products

“…(5) There are further interactions of substances, e.g. musk compounds are known to inhibit cellular xenobiotic export systems [17]. (6) Cross-reaction is known e.g.…”