Paraquat-induced cholesterol biosynthesis proteins dysregulation in human brain microvascular endothelial cells

Abstract

Despite Paraquat (PQ) being banned in several countries, it is still one of the most commonly used herbicides in agriculture. This compound is known to induce damaging effects on human and animal brain cells by generating Reactive Oxygen Species (ROS). However, there is few evidence of PQ effect on Human Brain Microvascular Endothelial Cells (HBMECs), one of the major component of the Blood–Brain Barrier (BBB). The present study aimed at unraveling biological mechanisms associated to the exposure of 1, 10 and 100 µM of PQ for 24 h on HBMECs. High-throughput mass spectrometry-based proteomics using data-independent acquisition (DIA) was applied. Biological pathway enrichment and cellular assays such as mitochondrial respiration and cholesterol level were performed to verify proteomics results. A total of 3753 proteins were quantified out of which 419 were significantly modulated by paraquat exposure. Biological pathway enrichment revealed the ubiquinone metabolism, a pathway directly linked to mitochondrial complex I proteins, confirming the well-known mechanism of PQ inducing oxidative stress. Additionally, this study also described the cholesterol biosynthesis modulation on HBMECs not yet described. In conclusion, our data indicate the toxic effect of PQ on HBMECs by downregulating proteins involved in mitochondrial complex I and cholesterol pathways.

Glyphosate vs. Glyphosate-Based Herbicides Exposure: A Review on Their Toxicity

“…Although presenting slow skin and oral absorption, its bioaccumulation in human organs, namely in lung or in kidney, has been shown to induce severe organ damage [ 18 , 19 ], and contact with the pesticide can induced skin irritation, nausea, diarrhea and abdominal pain [ 20 ]. In addition, unlike other xenobiotics, paraquat is not largely metabolized, and it was reported that it can reach neuronal tissue, permeating the blood–brain barrier, where its bioavailability increases with chronic exposure, leading to long-lasting effect [ 21 , 22 ]. When considering the nasal route, prolonged inhalation of paraquat can often induce fatal damage or long-term disorders, such as Parkinson’s disease [ 23 ].…”

Anthrahydroquinone‑2,6‑disulfonate attenuates PQ‑induced acute lung injury through decreasing pulmonary microvascular permeability via inhibition of the PI3K/AKT/eNOS pathway

“…Studies have demonstrated that PQ is absorbed into the bloodstream and first contacts endothelial cells, leading to oxidative stress, the inflammatory response and increased vascular permeability in pulmonary vascular endothelial cells. This induces pulmonary oedema, intra-alveolar haemorrhage and inflammatory cell infiltration ( 10 , 20 , 28 , 29 ), leading to death in severe cases ( 30 , 31 ). The mechanism by which PQ leads to endothelial cell dysfunction has not been clarified clinically and there is a lack of specific drugs and therapeutic options.…”

A potential mechanism clue to the periodic storm from microglia activation and progressive neuron damage induced by paraquat exposure

“…It has been confirmed that PQ is similar to that of 1‐methyl‐4‐phenyl pyridine ion (MPP + ) (the active metabolite of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine [MPTP]), a recognized dopaminergic neurotoxin 9 . In addition, PQ can penetrate through the blood–brain barrier, or combine with neutral amino acid transporters, 10 or modulate the pathways of cholesterol biosynthesis in human brain microvascular endothelial cells (HBMECs) and then induce neurotoxic effects 11 . It was reported that PQ could both induce neurotoxicity and cause a variety of central nervous system (CNS) dysfunctions, including Parkinson's disease (PD) 12,13 .…”

“…9 In addition, PQ can penetrate through the blood-brain barrier, or combine with neutral amino acid transporters, 10 or modulate the pathways of cholesterol biosynthesis in human brain microvascular endothelial cells (HBMECs) and then induce neurotoxic effects. 11 It was reported that PQ could both induce neurotoxicity and cause a variety of central nervous system (CNS) dysfunctions, including Parkinson's disease (PD). 12,13 At present, epidemiological investigations and clinical cases have confirmed that farmers and pesticide users who had a long-term and low-dose PQ exposure have 3.6 times higher risk than those who are not exposed to PQ.…”