Enhanced Disrupting Effect of Benzophenone-1 Chlorination Byproducts to the Androgen Receptor: Cell-Based Assays and Gaussian Accelerated Molecular Dynamics Simulations

Abstract

Benzophenone-1 (BP-1), one of the commonly used ultraviolet filters, has caused increasing public concern due to frequently detected residues in environmental and recreational waters. Its susceptibility to residual chlorine and the potential to subsequently trigger endocrine disruption remain unknown. We herein investigated the chlorination of BP-1 in swimming pool water and evaluated the endocrine disruption toward the human androgen receptor (AR). The structures of monochlorinated (P1) and dichlorinated (P2) products were separated and characterized by mass spectrometry and 1H–1H NMR correlation spectroscopy. P1 and P2 exhibited significantly higher antiandrogenic activity in yeast two-hybrid assays (EC50, 6.13 μM and 9.30 μM) than did BP-1 (12.89 μM). Our 350 ns Gaussian accelerated molecular dynamics simulations showed the protein dynamics in a long-time scale equilibrium, and further energy calculations revealed that although increased hydrophobic interactions are primarily responsible for enhanced binding affinities between chlorinated products and the AR ligand binding domain, the second chloride in P2 still hinders the complex motion because of the solvation penalty. The mixture of BP-1–P1–P2 elicited additive antiandrogenic activity, well fitted by the concentration addition model. P1 and P2 at 1 μM consequently downregulated the mRNA expression of AR-regulated genes, NKX3.1 and KLK3, by 1.7–9.1-fold in androgen-activated LNCaP cells. Because chlorination of BP-1 occurs naturally by residual chlorine in aquatic environments, our results regarding enhanced antiandrogenic activity and disturbed AR signaling provided evidence linking the use of personal care products with potential health risks.

Dissecting the Enantioselective Neurotoxicity of Isocarbophos: Chiral Insight from Cellular, Molecular, and Computational Investigations

“…However, the important π stacking is rather unstable between AChE and ( R )-isocarbophos, which is in line with the overall trend of conjugated effects obtained from MD simulation, that is, the conjugated effects of the AChE–( R )-isocarbophos adduct have a markedly weakening trend, whereas it is not observed to be distinctly changed in the AChE–( S )-isocarbophos complex. Besides, for the solvation free energy, we found that the polar solvation contribution (Δ G pol,sol ) played a major role in both neurotoxic reactions, and the energy data were 60.64 and 61.15 kcal mol –1 , respectively, the energy difference was Δ E = −0.51 kcal mol –1 , manifesting that the polar solvation contribution (Δ G pol,sol ) has almost the same influence on the free energy. , Clearly, these energy-scale results clarified the important reasons for the different biological affinities in the stereoselective toxic conjugations, namely, ( R )-isocarbophos has a lower neurotoxic reactivity to AChE compared with ( S )-isocarbophos. In other words, the toxic affinity of ( S )-isocarbophos with AChE is markedly better than that of ( R )-isocarbophos, and as an inhibitor, the strong modes of enantiomeric toxic action means that ( S )-isocarbophos has a more significant inhibitory effect on synaptic AChE, which is dovetailed with the results of SH-SY5Y nerve cell-based assays.…”

Recent developments in sunscreens based on chromophore compounds and nanoparticles

“…46 Fig. 14 In addition, avonoids and related phenylpropanoids, which accumulate as ultraviolet-absorbing compounds (27) and cause a decrease in the epidermal UV transmittance (TUV), are the main defenses used by plants against potentially harmful solar UV radiation. These compounds are also essential parts of the overall acclimation reaction of plants to shiing solar UV environments.…”

“…5a ). 27 However, the UV filter components in many sunscreen lotions include benzophenone-8 (BP-8) and benzophenone-3 (8, BP-3). In the adipogenesis model using the bone marrow of human mesenchymal stem cells (hBM-MSCs), the long-wave UV A filter avobenzone's obesogenic action was clarified.…”

Potential Disrupting Effects of Wastewater-Derived Disinfection Byproducts on Chinese Rare Minnow (Gobiocypris rarus) Transthyretin: An In Vitro and In Silico Study

“…For potential endocrine disrupting effects of DBPs, previous research focused mainly on determining the effects of some DBPs on various kinds of proteins and cell lines from humans and other mammals. − For example, the results from in vitro assay documented that DBPs could interfere hormone transporters (i.e., human transthyretin (hTTR) and human serum albumin), activate/inhibit hormone receptors such as human or rat estrogen receptor, − human androgen receptor, ,, peroxisome proliferator-activated receptor gamma (PPARγ), , and retinoid X receptor, and inhibit follicle growth and steroidogenesis in mouse ovarian antral follicles . The in vivo study also found that iodoacetic acid (IAA) could disrupt the rat thyroid system and elicit reproductive and developmental toxicity .…”