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Due to its endocrine-disrupting properties, bisphenol A (BPA) is being phased out from plastics, thermal paper and epoxy resins, and its replacements are being introduced into the market. Bisphenols are released into the environment, where they can undergo halogenation. Unlike BPA, the endocrine-disrupting potential of BPA analogues and their halogenated transformation products has not been extensively studied. The aim of this study was to evaluate the endocrine-disrupting potential of 18 BPA analogues and their halogenated derivatives by calculating affinities for 14 human nuclear receptors utilizing the Endocrine Disruptome and VirtualToxLab™ in silico tools. Our simulations identified AR, ERs, and GR as the most favorable targets of bisphenols and their derivatives. Several BPA analogues displayed a higher predicted potential for endocrine disruption than BPA. Our models highlighted BPZ and BPPH as the most hazardous in terms of predicted endocrine activities. Halogenation, in general, was predicted to increase the binding affinity of bisphenols for AR, ERβ, MR, GR, PPARγ, and TRβ. Notably, mono- or 2,2′-di-halogenated bisphenols exhibited the highest potential for endocrine disruption. In vitro corroboration of the obtained results should be the next milestone in evaluating the safety of BPA substitutes and their halogenated transformation products. [Display omitted] • Endocrine-disrupting potential of BPA, BPA analogues, and their halogenated derivatives was investigated in silico. • BPPH, BPTMC and BPZ were identified as the most potent endocrine disruptors. • Halogenation increases predicted binding affinity of bisphenols for AR, ERβ, MR, GR, PPARγ, and TRβ • Mono- or 2,2′-dihalogenated bisphenols exhibited the highest predicted endocrine disrupting potential. [ABSTRACT FROM AUTHOR]

The Aryl Hydrocarbon Receptor (AhR), a ligand-activated transcription factor, orchestrates responses to numerous structurally diverse endogenous and exogenous ligands. In addition to binding various xenobiotics, AhR also recognizes endocrine disruptors, particularly those featuring chlorinated or brominated aromatic structures. There is limited data available on the impact of common household and personal care product ingredients let alone their halogenated transformation products. Herein we bridge this knowledge gap by preparing a library of chlorinated and brominated parabens, bisphenols, UV filters, and nonylphenols. An evaluation of total of 125 compounds for agonistic and antagonistic activity on AhR unveiled a low micromolar agonist, Cl 2 BPAF with an EC 50 of 13 μM. Moreover, our study identified several AhR antagonists, with BrBzP emerging as the most potent with an IC 50 of 8.9 μM. To further investigate the functional implications of these compounds, we subjected the most potent agonist and antagonist to a functional assay involving cytokine secretion from peripheral blood mononuclear cells and compared their activity with the commercially available AhR agonist and antagonist. Cl 2 BPAF exhibited an overall immunosuppressive effect by reducing the secretion of proinflammatory cytokines, including IL-6, IFN-γ, and TNF-α, while BrBzP displayed opposite effects, leading to an increase of those cytokines. Notably, the immunomodulatory effects of Cl 2 BPAF surpassed those of ITE, a bona fide AhR agonist, while the impact of BrBzP exceeded that of CH223191, a bona fide AhR antagonist. In summary, our study underscores the potential influence of halogenated transformation products on the AhR pathway and, consequently, their role in shaping the immune responses. [Display omitted] • A comprehensive library of halogenated transformation products was prepared. • Halogenated derivatives can exhibit more pronounced AhR activity than parent compounds. • Cl 2 BPAF was the most potent agonist and BrBzP most potent antagonist of the series. • Cl 2 BPAF decreased LPS-induced inflammatory cytokine secretion from PBMCs. • BrBzP increased LPS-induced inflammatory cytokine secretion from PBMCs. [ABSTRACT FROM AUTHOR]

The everyday use of household and personal care products (HPCPs) generates an enormous amount of chemicals, of which several groups warrant additional attention, including: (i) parabens, which are widely used as preservatives; (ii) bisphenols, which are used in the manufacture of plastics; (iii) UV filters, which are essential components of many cosmetic products; and (iv) alkylphenol ethoxylates, which are used extensively as non-ionic surfactants. These chemicals are released continuously into the environment, thus contaminating soil, water, plants and animals. Wastewater treatment and water disinfection procedures can convert these chemicals into halogenated transformation products, which end up in the environment and pose a potential threat to humans and wildlife. Indeed, while certain parent HPCP ingredients have been confirmed as endocrine disruptors, less is known about the endocrine activities of their halogenated derivatives. The aim of this review is first to examine the sources and occurrence of halogenated transformation products in the environment, and second to compare their endocrine-disrupting properties to those of their parent compounds (i.e., parabens, bisphenols, UV filters, alkylphenol ethoxylates). Albeit previous reports have focused individually on selected classes of such substances, none have considered the problem of their halogenated transformation products. This review therefore summarizes the available research on these halogenated compounds, highlights the potential exposure pathways, and underlines the existing knowledge gaps within their toxicological profiles. [Display omitted] • Halogenated transformation products are found in the environment and in human tissues. • Halogenated derivatives disrupt different hormonal pathways than parent compounds. • Halogenation in general decreases estrogen and androgen receptor activation. • Introduction of halogens increases activation of thyroid and aryl hydrocarbon receptors. [ABSTRACT FROM AUTHOR]