Jingpeng Wang

Side Chains of Parabens Modulate Antiandrogenic Activity: In Vitro and Molecular Docking Studies

Parabens have been widely used in packaged foods, pharmaceuticals, and personal-care products. Considering their potential hydrolysis, we herein investigated structural features leading to the disruption of human androgen receptor (AR) and whether hydrolysis could alleviate such effects using the recombinant yeast two-hybrid assay. Parabens with an aryloxy side chain such as benzyl paraben and phenyl paraben have the strongest antiandrogenic activity. The antiandrogenic activity of parabens with alkyloxyl side chains decreases as the side chain length increases from 1 to 4, and no antiandrogenic effect occurred for heptyl, octyl, and dodecyl parabens with the number of alkoxyl carbon atoms longer than 7. The antiandrogenic activity of parabens correlates significantly with their binding energies (R2 = 0.84, p = 0.01) and were completely diminished after the hydrolysis, particularly for parabens with aryloxy side chains. The Km for the hydrolysis of parabens with aromatic moiety side chain is 1 order of magnitude higher than that of the parabens with alkyl side chains. Both in vitro and in silico data, for the first time, suggest parabens with aromatic side chains are less prone to hydrolysis. Our results provide an insight into risk of various paraben and considerations for design of new paraben-related substitutes.

Thyroid Disruption by Bisphenol S Analogues via Thyroid Hormone Receptor β: in Vitro, in Vivo, and Molecular Dynamics Simulation Study

Bisphenol S (4-hydroxyphenyl sulfone, BPS) is increasingly used as a bisphenol A (BPA) alternative. The global usage of BPS and its analogues (BPSs) resulted in the frequent detection of their residues in multiple environmental media. We investigated their potential endocrine-disrupting effects toward thyroid hormone receptor (TR) β. The molecular interaction of BPSs toward TRβ ligand binding domain (LBD) was probed by fluorescence spectroscopy and molecular dynamics (MD) simulations. BPSs caused the static fluorescence quenching of TRβ LBD. The 100 ns MD simulations revealed that the binding of BPSs caused significant changes in the distance between residue His435 at helix 11(H11) and residue Phe459 at H12 in comparison to no ligand-bound TRβ LBD, indicating relative repositioning of H12. The recombinant two-hybrid yeast assay showed that tetrabromobisphenol S (TBBPS) and tetrabromobisphenol A (TBBPA) have potent antagonistic activity toward TRβ, with an IC10 of 10.1 and 21.1 nM, respectively. BPS and BPA have the antagonistic activity with IC10 of 312 and 884 nM, respectively. BPSs significantly altered the expression level of mRNA of TRβ gene in zebrafish embryos. BPS and TBBPS at environmentally relevant concentrations have antagonistic activity toward TRβ, implying that BPSs are not safe BPA alternatives in many BPA-free products. Future health risk assessments for TR disruption and other adverse effects should focus more on the structure-activity relationship in the design of environmentally benign BPA alternatives.

In vitro and in silico investigations of the binary-mixture toxicity of phthalate esters and cadmium (II) to Vibrio qinghaiensis sp.-Q67

Phthalate esters (PAEs) are widely used as plasticizers and have become one of the emerging contaminants with an increasing public concern. The residues of PAEs frequently co-exist with heavy metals such as cadmium (Cd) in waters; however, their joint ecotoxicity remains largely unknown. We herein investigated the single and joint toxicity of commonly used PAEs and Cd using freshwater luminescent bacteria Vibrio qinghaiensis sp.-Q67. The median effective concentration (EC50) of benzyl butyl phthalate (BBP), dibutyl phthalate (DBP), diethyl phthalate (DEP), dimethyl phthalate (DMP), diisooctyl phthalate (DIOP) and di-n-octyl phthalate (DOP) were determined to be in the range from 134.4mg/L to as high as 1000mg/L, indicating very weak toxicity to Vibrio qinghaiensis sp.-Q67. The toxicity of single PAEs showed a significant linear relationship with Log Kow, indicating the dependence of the elevated toxicity on the increasing hydrophilicity. The toxicity of binary mixture of PAEs was further evaluated in silico using the independent action (IA) model and concentration addition (CA) model. DMP-DEP, DEP-DBP or DMP-DBP exhibited antagonistic effects with the toxic unit value higher than 1.2. The CA and IA models poorly predicted the joint toxicity of DMP-DEP, DEP-DBP or DMP-DBP. The joint toxicity of the binary mixtures of DMP, DEP or DBP with Cd was simple additive as predicted by the CA and IA models. Our results indicated the potentially higher risk of PAEs in the presence of Cd, emphasizing the importance of determining the impact of their joint effects on aquatic organisms. The integrated in vitro and in silico methods employed in this study will be beneficial to study the joint toxicity and better assess the aquatic ecological risk of PAEs.

Temporal variation of oxidative potential of water soluble components of ambient PM2.5 measured by dithiothreitol (DTT) assay

The exposure to ambient fine particulate matter (PM2.5) can induce oxidative stress, contributing to global burden of diseases. The evaluation of the oxidative potential (OP) of PM2.5 is thus critical for the health risk assessment. We collected ambient PM2.5 samples in Hangzhou city, China for four consecutive quarters in the year 2017 and investigated the oxidation property of PM2.5 components by the dithiothreitol (DTT) assay. The annual mean of ambient PM2.5 mass concentrations in 2017 was 63.05 μg m-3 (median: 57.34, range: 6.67-214.33 μg m-3) with the significant seasonal variations ranking as winter > spring > summer > autumn. Secondary inorganic aerosol (SIA) species including SO42-, NO3- and NH4+ totally account for >50% of PM2.5 mass. The annual mean volume-normalized DTT activity (DTTv) showed a relatively high value of 0.62 nmol/min/m3 (median: 0.62, range: 0.11-1.66 nmol/min/m3) and DTTv of four seasons was roughly at the same level, indicating a high annual exposure level of ambient PM2.5. SIA species were correlated well with the corresponding DTTv and showed significant diurnal variations with strong or moderate correlations at day and weak correlations at night, suggesting strong secondary formation in daytime with contribution to the particulate OP. The annual mean mass-normalized DTT activity (DTTm) had a relatively low value of 6.39 pmol/min/μg (median: 5.63, range: 1.99-22.70 pmol/min/μg), indicating low intrinsic oxidative toxicity. The DTTm of four seasons ranked as autumn > winter > spring > summer, indicating seasonal variations of the DTT-active components. The PM2.5 mass concentration is more related to exposure levels than intrinsic properties of components, while OP is determined by the components rather than PM2.5 mass concentration. Our results provide an insight into reactive oxygen species-induced health risk of PM2.5 exposure and decision for subsequent emission control.