Search

As alternatives of perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimeric acid (HFPO-DA) and trimeric acid (HFPO-TA) have been detected increasingly in environmental media and even humans. They have been shown to exhibit reproductive toxicity to model species, but their effects on human remain unclear due to the knowledge gap in their mode of action. Herein, (anti-)androgenic effects of the two HFPOs and PFOA were investigated and underlying toxicological mechanism was explored by combining zebrafish test, cell assay and molecular docking simulation. Exposure of juvenile zebrafish to the chemicals during sex differentiation promoted feminization, with HFPO-TA acting at an environmental concentration of 1 μg/L. The chemicals inhibited proliferation of human prostate cells and transcriptional activity of human and zebrafish androgen receptors (AR), with HFPO-TA displaying the strongest potency. Molecular docking revealed that the chemicals bind to AR in a conformation similar to a known AR antagonist. Combined in vivo, in vitro and in silico results demonstrated that the chemicals disrupted sex differentiation likely by antagonizing AR-mediated pathways, and provided more evidence that HFPO-TA is not a safe alternative to PFOA.

Metalaxyl (MET) and myclobutanil (MYC) are two widely used chiral fungicides that may pose health risks to non-occupationally exposed populations. Here, the two fungicides were enantiomer-specific quantified in the dietary food and urine of residents in an Eastern China city, to determine the exposure and excretion of these contaminants in different populations. Results indicate that residues of MET and MYC varied with different food items at 0.42–0.86 ng/g fresh weight (FW) and 0.18–0.33 ng/g FW, respectively. In urine samples, the residual levels after creatinine adjusting (CR) ranged from 10.2 to 1715.4 ng/g CR for MET and were below the detection limit up to 320.7 ng/g CR for MYC. Significant age- and gender-related differences were separately found in urinary MET and MYC of different populations. Monte-Carlo simulations suggested that children had higher daily dietary intake (DDI) but lower urinary excretion (DUE) rates than youths, and thus may suffer higher body burdens. The residues of antifungally ineffective enantiomers (S-MET and R-MYC) were slightly higher than their antipodes in foods. Moreover, the enantiomer-selective urinary excretion resulted in higher retention of S-MET and R-MYC in the human body. Our results suggest that both dietary intake and urinary excretion should be enantiomer-specifically considered when assessing the exposure risk and body burden of chiral fungicides in the non-occupationally exposed population. Furthermore, substitutive application of enantiomer-enriched fungicide formulations can not only benefit the antifungal efficacy but also be safer for human health.

Several studies have indicated metabolic function disruption effects of bisphenol analogues through peroxisome proliferator-activated receptor (PPAR) alpha and gamma pathways. In the present study, we found for the first time that PPARβ/δ might be a novel cellular target of bisphenol analogues. By using the fluorescence competitive binding assay, we found seven bisphenol analogues could bind to PPARβ/δ directly, among which tetrabromobisphenol A (TBBPA, 18.38-fold) and tetrachlorobisphenol A (TCBPA, 12.06-fold) exhibited stronger binding affinity than bisphenol A (BPA). In PPARβ/δ-mediated luciferase reporter gene assay, the seven bisphenol analogues showed transcriptional activity toward PPARβ/δ. Bisphenol AF (BPAF), bisphenol F (BPF) and bisphenol B (BPB) even showed higher transcriptional activity than BPA, while TBBPA and TCBPA showed comparable activity with BPA. Moreover, in human liver HL-7702 cells, the bisphenol analogues promoted the expression of two PPARβ/δ target genes PDK4 and ANGPTL4. Molecular docking simulation indicated the binding potency of bisphenol analogues to PPARβ/δ might depend on halogenation and hydrophobicity and the transcriptional activity might depend on their binding affinity and hydrogen bond interactions. Overall, the PPARβ/δ pathway may provide a new mechanism for the metabolic function disruption of bisphenol analogues, and TBBPA and TCBPA might exert higher metabolic disruption effects than BPA via PPARβ/δ pathway.