Disruption of zebrafish sex differentiation by emerging contaminants hexafluoropropylene oxides at environmental concentrations via antagonizing androgen receptor pathways.

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.

Activation of estrogen-related receptor: An alternative mechanism of hexafluoropropylene oxide homologs estrogenic effects.

Perfluorooctanoic acid (PFOA) alternatives such as hexafluoropropylene oxide homologs (HFPOs) cause concern due to increased occurrence in the environment as well as potential bioaccumulation and toxicity. HFPOs have been demonstrated to activate the estrogen receptor (ER) pathway. The ER pathway is homologous and connected to the estrogen-related receptor (ERR) pathway, but HFPOs effects on the ERR pathway have not been studied. Hence, we assessed the potential estrogenic effects of HFPOs via ERRγ pathway. In vitro assays revealed that HFPO dimeric, trimeric, and tetrameric acids (HFPO-DA, -TA, and -TeA, respectively), acted as ERRγ agonists, activating the transcription of both human and zebrafish ERRγ at low concentrations, but inhibiting zebrafish ERRγ at high concentrations. We also found that HFPO-TA promoted the human endometrial cancer cells (Ishikawa cells) proliferation via ERRγ/EGF, Cyclin D1 pathway. The HFPO-TA-induced proliferation of Ishikawa cells was inhibited by co-exposure with a specific antagonist of ERRγ, GSK5182. In vivo exposure of female zebrafish to HFPO-TA disturbed sex hormone levels, interfered with the gene expression involved in estrogen synthesis and follicle regulation, and caused histopathological lesions in the ovaries, which were similar to those induced by a known ERRγ agonist GSK4716. Taken together, this study revealed a new mechanism concerning the estrogenic effect of HFPOs via activation of the ERRγ pathway.

A novel heterometallic ruthenium-silver complex as potential antitumor agent: Studies on its synthesis, in vitro assays and interactions with biomolecular targets.

Certain ruthenium compounds are found to be potent growth inhibitors for cancer cells. In the current study, a novel ruthenium-triphenylphosphine (PPh3) cation and silver-2-mercapto nicotinate acid (H2mna) anion complex (RSC) was synthesized, and its molecular structure was determined by IR, NMR and X-ray crystallography. Biological assays revealed that RSC strongly inhibited the viability of MCF-7 and MDA-MB-231 cells with IC50 values of 9.6±1.1 and 7.5±0.8 µM, respectively, and significantly blocked their migration rates. Ultraviolet spectroscopy and fluorescence emission experiments demonstrated that RSC interacted with BSA, but not DNA. Further studies on [Ag6(Hmna)2(mna)4]4- binding with BSA and DNA found the anion did not interact with these biomolecules, indicating that RSC exerted its biological functions through its ruthenium-PPh3 complex (RTC) moiety, and molecular docking provided additional evidence supporting this result. Fluorescence resonance energy transfer showed that the number of binding sites (n) and binding constant of RTC-BSA complex were 1 and 8.60 × 104 M-1 at 310K, suggesting a strong interaction between RTC and BSA. The thermodynamic parameters ΔG0, ΔH0 and ΔS0 of the binding were calculated, and it was demonstrated that the binding of RTC with BSA was enthalpy-driven, and the main forces between RTC and BSA were electrostatic force and hydrogen bonding. Molecular docking showed that the binding site of BSA with RSC was located on the interface between the domains IIA and IIB of the protein. The present study sheds light on that a ruthenium mono-coordinated with PPh3 complex could help to design and develop a new class of antitumor drugs.