Benzotriazole Ultraviolet Stabilizers Show Potent Activities as Human Aryl Hydrocarbon Receptor Ligands

Abstract

Benzotriazole ultraviolet stabilizers (BUVSs) used in consumer products are raising concerns as new pollutants in the aquatic environment. We determined the agonistic activities of eight BUVSs and a chemically distinct UV absorber (4-methylbenzylidinecamphor) toward the human aryl hydrocarbon receptor (AhR) and thyroid hormone receptors alpha and beta. Although none of the BUVSs showed ligand activity against the thyroid hormone receptors, four of them (UV-P, UV-9, UV-326, and UV-090) showed significant AhR ligand activity. Their half-maximal effective concentrations (EC50) were 130 nM for UV-P, 460 nM for UV-9, and 5.1 μM for UV-090 (a value for UV-326 could not be determined). Of the numerous AhR ligands, it is well-known that those considered nontoxic are quickly metabolized by enzymes such as CYP1A1, which destroys their ability to function as ligands. Accordingly, we established a new yeast assay for simultaneous monitoring of both the strength of AhR ligand activity and ligand degradation by CYP1A1. We found the AhR ligand activities of the above four BUVSs to be stable in the presence of CYP1A1; therefore, they have the potential to accumulate and exert potent physiological effects in humans, analogous to polycyclic aromatic hydrocarbons and dioxins, which are known stable and toxic ligands.

Benzotriazole ultraviolet stabilizers alter the expression of the thyroid hormone pathway in zebrafish (Danio rerio) embryos

“…Although BUVSs have not shown ligand activity toward the human thyroid hormone receptors (Nagayoshi et al, 2015), there is evidence that these compounds may adversely affect the thyroid system of vertebrates, for example, suppression of thra in zebrafish embryos following exposure to 690 mg/L UV-P (Fent et al, 2014).…”

“…BUVSs have been applied in textiles, plastics, building materials, automobile components, paint, and sports equipment to prevent yellowing and degradation (Nakata et al, 2009). In addition, they are also used in personal-hygiene products, including body lotions, creams, shampoos, fragrances, and sunscreens (Kim et al, 2011a;Nagayoshi et al, 2015). Due to their high production volume and wide application, BUVSs have been frequently detected in various environmental matrices such as municipal waste water, sewage sludge, sediment, soil, and indoor dust (Lai et al, 2014;Ramos et al, 2016;Wang et al, 2013a).…”

“…Recent studies in mammals and fish have reported on their endocrine disrupting effects (Fent et al, 2014;Kawamura et al, 2003;Morohoshi et al, 2005;Nagayoshi et al, 2015;Zhuang et al, 2017). UV-P, UV-9, UV-326, and UV-090 show significant ligand activity against human aryl hydrocarbon receptor (AhR) (Nagayoshi et al, 2015).…”

“…Recent studies in mammals and fish have reported on their endocrine disrupting effects (Fent et al, 2014;Kawamura et al, 2003;Morohoshi et al, 2005;Nagayoshi et al, 2015;Zhuang et al, 2017). UV-P, UV-9, UV-326, and UV-090 show significant ligand activity against human aryl hydrocarbon receptor (AhR) (Nagayoshi et al, 2015). In addition, biotransformation of BUVSs has been shown to influence their anti-androgenic activities, thus bioactivation/biotransformation appear to be important mechanisms that determine their toxicity and endocrine disrupting actions (Zhuang et al, 2017).…”

“…Additionally, mRNA level of thyroid hormone receptor a in zebrafish embryos was observed to be significantly decreased following exposure to 690 mg/L UV-P (Fent et al, 2014), whereas, none of the tested BUVSs showed ligand activity against the human thyroid hormone receptors (Nagayoshi et al, 2015). Thyroid hormones (THs) play fundamental roles in regulating development, differentiation, and metabolism of all vertebrates (Power et al, 2001).…”