Effects of Cadmium on ZO-1 Tight Junction Integrity of the Blood Brain Barrier

Abstract

Cadmium (Cd) is a highly toxic environmental pollutant released from the smelting and refining of metals and cigarette smoking. Oral exposure to cadmium may result in adverse effects on a number of tissues, including the central nervous system (CNS). In fact, its toxicity has been related to neurological disorders, as well as neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Under normal conditions, Cd barely reaches the brain in adults because of the presence of the blood–brain barrier (BBB); however, it has been demonstrated that Cd-dependent BBB alteration contributes to pathogenesis of neurodegeneration. However, the mechanism underlying Cd-dependent BBB alteration remain obscure. Here, we investigated the signaling pathway of Cd-induced tight junction (TJ), F-actin, and vimentin protein disassembly in a rat brain endothelial cell line (RBE4). RBE4 cells treated with 10 μM cadmium chloride (CdCl2) showed a dose- and time-dependent significant increase in reactive oxygen species (ROS) production. This phenomenon was coincident with the alteration of the TJ zonula occludens-1 (ZO-1), F-actin, and vimentin proteins. The Cd-dependent ROS increase elicited the upregulation of GRP78 expression levels, a chaperone involved in endoplasmic reticulum (ER) stress that induces caspase-3 activation. Further signal profiling by the pannexin-1 (PANX1) specific inhibitor 10Panx revealed a PANX1-independent increase in ATP spillage in Cd-treated endothelial cells. Our results point out that a ROS-dependent ER stress-mediated signaling pathway involving caspase-3 activation and ATP release is behind the BBB morphological alterations induced by Cd.

Cadmium-Induced Oxidative Stress: Focus on the Central Nervous System

“…Accordingly, with Tobwala and colleagues, recently, some authors demonstrated no Cd-dependent ZO-1 TJ protein expression alteration in a rat brain endothelial cell (RBE4) line. Nevertheless, the same authors clearly demonstrated an altered distribution of the ZO-1 TJ as well as the formation of F-actin stress fibers and an abnormal vimentin localization upon Cd administration [131].…”

“…Once Cd induces BBB disruption and permeability increase, it can penetrate and accumulate in the CNS, thus leading to cerebral damage [131].…”

Enhanced Zinc Intake Protects against Oxidative Stress and Its Consequences in the Brain: A Study in an In Vivo Rat Model of Cadmium Exposure

“…Although so far the unfavorable influence of Cd on the nervous system has been revealed in only a few epidemiological studies [ 29 , 30 , 31 ], this effect has been reported in some investigations carried out in animal models [ 18 , 22 , 31 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. The injurious action of this heavy metal on the central nervous system is multidirectional and complex [ 18 , 22 , 31 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. Literature data indicate that Cd may stimulate the generation of reactive oxygen species (ROS) leading to oxidative stress and interact with essential elements (including calcium—Ca) in the nervous tissue, as well as impair neurogenesis, induce apoptosis of neurons, and influence the glutamatergic system, gene expression, and homeostasis of neurotransmitters, including acetylcholinesterase [ 18 , 22 , 31 , 34 , 35 , 36 , 37 , 38 , 39 , 40 …”

“…The injurious action of this heavy metal on the central nervous system is multidirectional and complex [ 18 , 22 , 31 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. Literature data indicate that Cd may stimulate the generation of reactive oxygen species (ROS) leading to oxidative stress and interact with essential elements (including calcium—Ca) in the nervous tissue, as well as impair neurogenesis, induce apoptosis of neurons, and influence the glutamatergic system, gene expression, and homeostasis of neurotransmitters, including acetylcholinesterase [ 18 , 22 , 31 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. It is known that lipids are among cellular macromolecules most vulnerable to oxidative modifications [ 38 , 39 , 49 ] and therefore, the brain tissue, due to the abundance of lipids and high oxygen utilization, is especially susceptible to damage by pro-oxidants via the oxidative stress-related mechanisms [ 22 , 38 , 39 , 50 ].…”

Cadmium-Induced Cytotoxicity: Effects on Mitochondrial Electron Transport Chain

“…A recent meta-analysis has suggested that increased levels of Cd in human serum might play a pivotal role in neurodegenerative disorder progression (Xu et al, 2018). In vitro and in vivo studies demonstrated a direct role of Cd in ROS production and endoplasmic reticulum stress (Shukla et al, 1996;Branca et al, 2019a), ultimately leading to the impairment of blood-brain barrier (BBB) integrity. Indeed, once the BBB integrity is compromised, heavy metals and other toxicants can enter the CNS and activate glial cells, causing brain inflammation and neural degeneration (Branca et al, 2020).…”