Perfluorooctane sulfonate promotes the migration of colorectal cancer cells by inducing epithelial-mesenchymal transition.

The potential association between colorectal cancer (CRC) and environmental pollutants is worrisome. Previous studies have found that some perfluoroalkyl acids, including perfluorooctane sulfonate (PFOS), induced colorectal tumors in experimental animals and promoted the migration of and invasion by CRC cells in vitro, but the underlying mechanism is unclear. Here, we investigated the effects of PFOS on the proliferation and migration of CRC cells and the potential mechanisms involving activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition (EMT). It was found that PFOS promoted the growth and migration of HCT116 cells at non-cytotoxic concentrations and increased the mRNA expression of the migration-related angiogenic cytokines vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In a mechanistic investigation, the up-stream signal pathway PI3K/Akt-NF-κB was activated by PFOS, and the process was suppressed by LY294002 (PI3K/Akt inhibitor) and BAY11-7082 (NF-κB inhibitor) respectively, leading to less proliferation of HCT116 cells. Furthermore, matrix metalloproteinases (MMP) and EMT-related markers were up-regulated after PFOS exposure, and were also suppressed respectively by LY294002 and BAY11-7082. Moreover, the up-regulation of EMT markers was suppressed by a MMP inhibitor GM6001. Taken together, our results indicated that PFOS promotes colorectal cancer cell migration and proliferation by activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition. This could be a potential toxicological mechanism of PFOS-induced malignant development of colorectal cancer.

Antibiotics disrupt lipid metabolism in zebrafish (Danio rerio) larvae and 3T3-L1 preadipocytes.

Antibiotics are emerging environmental contaminants with wide attention due to their high consumption and pseudo-persistence in the environment. They have been shown to induce obesity or obesity-related metabolic diseases in experimental animals, but the underlying toxicological mechanisms remain unclear. Here, the disruptive effects of four commonly used antibiotics, namely doxycycline (DC), enrofloxacin (ENR), florfenicol (FF) and sulfamethazine (SMT) on lipid metabolism were investigated in zebrafish (Danio rerio) larvae and murine preadipocyte cell line. Triglyceride (TG) content was reduced after 1 ng/L DC or ENR exposure but was increased at higher concentrations up to 100 mg/L. FF increased and SMT reduced TG content but did not show any concentration dependence. None of the antibiotics had any significant effect on total cholesterol (TC) content in zebrafish except 100 µg/L SMT. Expression levels of 8 lipid metabolism-related genes were also quantified. SMT was most disruptive by up-regulating six genes, followed by FF which up-regulated four genes and down-regulated one gene, whereas DC and ENR both up-regulated one gene. In 3T3-L1 preadipocytes, ENR, FF, and SMT in general increased TG content, while 100 mg/L FF reduced TG substantially. DC did not show any effect up to 10 mg/L, at which TG increased significantly. FF and SMT increased TC slightly at low concentrations but reduced it at high concentrations, whereas TC, DC and ENR had no effect at any tested concentrations. Gene expression measurement also indicated that SMT was most disruptive, followed by FF, DC, and ENR. Reporter gene assays showed that only SMT inhibited the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). The above experimental results and clustering analysis demonstrate that the four antibiotics exerted disruption on lipid metabolism through different mechanisms, and one of the mechanisms for SMT may be inhibition of PPARγ transcriptional activity.

Perfluorooctanoic acid alternatives hexafluoropropylene oxides exert male reproductive toxicity by disrupting blood-testis barrier.

As alternatives to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide (HFPO) homologues, including hexafluoropropylene oxide dimer acid (HFPO-DA), hexafluoropropylene oxide trimer acid (HFPO-TA), and hexafluoropropylene oxide tetramer acid (HFPO-TeA), have attracted widespread attention recently due to their environmental ubiquity and high potential for bioaccumulation and toxicity. In the present study, a set of in vivo mouse and in vitro mouse testicular Sertoli TM4 cell experiments were employed to explore the male reproductive toxicity and underlying mechanisms of HFPO homologues on blood-testis barrier. Tissue and permeability analyses of mice testes after 28-day treatment with 5 mg/kg/day HFPO-DA or PFOA, or 0.05 mg/kg/day HFPO-TA or HFPO-TeA indicated that there was an increase in the degradation of TJ protein occludin in mice with a disrupted blood-testis barrier (BTB). Following exposure to 100 µM HFPO-DA, HFPO-TA or 10 µM PFOA, HFPO-TeA, transepithelial electrical resistance measurements of TM4 cells also indicated BTB disruption. Additionally, as a result of the exposure, matrix metalloproteinase-9 expression was enhanced through activation of p38 MAPK, which promoted the degradation of occludin. On the whole, the results indicated HFPO homologues and PFOA induced BTB disruption through upregulation of p-p38/p38 MAPK/MMP-9 pathway, which promoted the degradation of TJ protein occludin and caused the disruption of TJ.