PFOS Disturbs BDNF-ERK-CREB Signalling in Association with Increased MicroRNA-22 in SH-SY5Y Cells

Abstract

Perfluorooctane sulfonate (PFOS), a ubiquitous environmental pollutant, is neurotoxic to mammalian species. However, the underlying mechanism of its neurotoxicity was unclear. We hypothesized that PFOS suppresses BDNF expression to produce its neurotoxic effects by inhibiting the ERK-CREB pathway. SH-SY5Y human neuroblastoma cells were exposed to various concentrations of PFOS to examine the role of the BDNF-ERK-CREB signalling pathway in PFOS-induced apoptosis and cytotoxicity. Furthermore, to ascertain the mechanism by which PFOS reduces BDNF signalling, we examined the expression levels of miR-16 and miR-22, which potentially regulate BDNF mRNA translation at the posttranscriptional level. Results indicated that PFOS significantly decreased cell viability and induced apoptosis in SH-SY5Y cells. In addition, BDNF and pERK protein levels decreased after PFOS treatment; however, pCREB protein levels were significantly elevated in PFOS treated groups. TrkB protein expression increased in the 10 μM and 50 μM PFOS groups and significantly decreased in the 100 μM PFOS group. Our results demonstrated that PFOS exposure decreased miR-16 expression and increased miR-22 expression, which may represent a possible mechanism by which PFOS decreases BDNF protein levels. PFOS may inhibit BDNF-ERK-CREB signalling by increasing miR-22 levels, which may, in part, explain the mechanism of PFOS neurotoxicity.

Porcine epidemic diarrhea virus infections induce apoptosis in Vero cells via a reactive oxygen species (ROS)/p53, but not p38 MAPK and SAPK/JNK signalling pathways

“…Xu, et al Veterinary Microbiology 232 (2019) 1-12 during PEDV infection, however, treatment with an excessive amount of inhibitors may have adverse effects on cell activity and cause cytotoxicity that disturbs normal cell metabolism. Similar examples can be found in rafoxanide against MM cells (Xiao et al, 2019), PFOS against SH-SY5Y cells (Li et al, 2015) and plumbagin against MCF-7 (A), SK-OV-3 (B), and MCF-10A (De et al, 2019). Thus, to exclude the effect of inhibitors on the toxicity of cells, we tested the inhibitory effect of cells in the presence of inhibitor and antioxidant treatment for 24 h. Results showed that treatment with 10 μM PFT-α, 10 μM SB203580, 10 μM SP600125, 5 mM NAC and 50 μM PDTC had no inhibitory effect on cell viability, which indicated that there was no significant influence in cells treated with inhibitor and antioxidant for 24 h. Therefore, the influence of signalling inhibitors on cells can be excluded, in other words, all changes in those proteins tested were caused by PEDV.…”

Brain-Derived Neurotrophic Factor Mediated Perfluorooctane Sulfonate Induced-Neurotoxicity via Epigenetics Regulation in SK-N-SH Cells

“…Previous studies revealed that rat prenatal PFOS exposure decreased protein expression of BDNF on postnatal day (PND) 35 in the hippocampus tissue of the offspring, but increased the mRNA levels of BDNF [10]. Our previous studies also suggested that PFOS could reduce mRNA and protein levels of BDNF in SH-SY5Y cells [11]. However, the exact mechanism is not very clear and needs more investigation.…”

Developing integrated PBPK/PD coupled mechanistic pathway model (miRNA-BDNF): An approach towards system toxicology

“…Muiños-Gimeno et al, (2011) reported the involvement of miRNA-22 associated panic disorders in the Spanish and North European population. Later, the transcriptomic analysis studied by Li et al, (2015) in SH-SY5Y cell line also found the involvement of miRNA-22 dependent decrease in the BDNF level and neuronal cell survivability. The miRNAs are turning out to be significant regulators of mRNAs and the related proteins.…”

“…The several mechanisms were hypothesized for the PFOS causing development neurotoxicity disorders such as oxidative stress, altering neurotransmitters level and upregulation and downregulation of apoptotic and pro-survival factors from various animals and cell line studies (Long et al, 2013;Chen et al, 2014;Yu et al, 2016). In a recent study, it was found that PFOS can decrease the neuronal cell survivability by altering the level of miRNA in human neuroblastoma cell line (Li et al, 2015). This could be an important mechanism of PFOS as it has been seen that miRNAs regulate the proteins level by regulating their mRNAs expression level.…”

“…It has an assumption that the in-vitro area under the curve (AUC), calculated by multiplying dose with the total duration of exposure, would be similar with the AUC of target in-vivo organ (in this case Brain). Li et al, (2015) in-vitro studies on SH-SY5Y cell line was selected, where a decrease in neuronal cell survivability found to depend on miRNA and BDNF. In Li et al, an experiment they used 12 in-vitro doses (6 doses each for 24hr and 48 hr) for that corresponding in vivo doses was determined.…”