Triclocarban, Triclosan, Bromochlorophene, Chlorophene, and Climbazole Effects on Nuclear Receptors: An in Silico and in Vitro Study

Abstract

BACKGROUND: Endocrine-disrupting chemicals can interfere with hormonal homeostasis and have adverse effects for both humans and the environment. Their identification is increasingly difficult due to lack of adequate toxicological tests. This difficulty is particularly problematic for cosmetic ingredients, because in vivo testing is now banned completely in the European Union. OBJECTIVES: The aim was to identify candidate preservatives as endocrine disruptors by in silico methods and to confirm endocrine receptors' activities through nuclear receptors in vitro. METHODS: We screened preservatives listed in Annex V in the European Union Regulation on cosmetic products to predict their binding to nuclear receptors using the Endocrine Disruptome and VirtualToxLab™ version 5.8 in silico tools. Five candidate preservatives were further evaluated for androgen receptor (AR), estrogen receptor (ERa), glucocorticoid receptor (GR), and thyroid receptor (TR) agonist and antagonist activities in cellbased luciferase reporter assays in vitro in AR-EcoScreen, hERa-HeLa-9903, MDA-kb2, and GH3.TRE-Luc cell lines. Additionally, assays to test for false positives were used (nonspecific luciferase gene induction and luciferase inhibition). RESULTS: Triclocarban had agonist activity on AR and ERa at 1 lM and antagonist activity on GR at 5 lM and TR at 1 lM. Triclosan showed antagonist effects on AR, ERa, GR at 10 lM and TR at 5 lM, and bromochlorophene at 1 lM (AR and TR) and at 10 lM (ERa and GR). AR antagonist activity of chlorophene was observed [inhibitory concentration at 50% (IC 50) IC 50 = 2:4 lM], as for its substantial ERa agonist at >5 lM and TR antagonist activity at 10 lM. Climbazole showed AR antagonist (IC 50 = 13:6 lM), ERa agonist at >10 lM, and TR antagonist activity at 10 lM. DISCUSSION: These data support the concerns of regulatory authorities about the endocrine-disrupting potential of preservatives. These data also define the need to further determine their effects on the endocrine system and the need to reassess the risks they pose to human health and the environment.

Comprehensive insight into triclosan—from widespread occurrence to health outcomes

“…TCS acts as estrogenic agonist and antagonist based on the experiments conducted on various breast cancer cells (Huang et al 2014b ; Henry and Fair 2013 ). Thus, antagonist effects of TCS were also observed on glucocorticoid, androgenic and thyroid receptors (Kenda et al 2020 ). Different mechanisms of in vitro disruption of thyroid homeostasis were suggested such as dose–response inhibition of T4 to T3 conversion (Butt et al 2011 ) as well as a non-competitive inhibition of iodide uptake in rat thyroid follicular cells and thyroid peroxidase activity in rat microsomes (Wu et al 2016 ).…”

Chronic Exposure to Climbazole Induces Oxidative Stress and Sex Hormone Imbalance in the Testes of Male Zebrafish

“…As shown in Figure a, CBZ significantly decreased the E2 concentration in zebrafish testes from the M-group, while the reductions in T and 11-KT levels were found in all CBZ-exposed groups ( p < 0.05). Kenda et al (2020) confirmed that CBZ is an androgen receptor antagonist, which competes with endogenous androgens for androgen receptors and thereby blocks androgens exerting their physiological functions . T and 11-KT are the most active androgens in fish, and they are required to participate in the spermatogenesis of males. , It has been reported that the reduction of T and 11-KT may change the sex differentiation, reproductive behavior, and population of fish .…”

A Simple Method for the Determination of Pharmaceutical and Personal Care Products in Fish Tissue Based on Matrix Solid-Phase Dispersion

“…TCC is widely used as an antimicrobial agent in personal care products, with an annual consumption of 200–400 tons in the United States . However, it is an endocrine-disrupting chemical that leads to adverse reproductive and developmental effects . The target analytes in this study are not only widely used in industries and daily life but also frequently detected in the aquatic environment …”