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Chemistry, Analytical
Brominated flame retardants (BFR) have been extensively applied to reduce the flammability of some commercial products such as furniture, circuit boards, textiles, polystyrene foams, epoxy resins, and padding materials [1,2,3], because of their potency and ability to meet safety standards. These BFRs include chemicals, such as chlorine, bromine, and phosphorus. Currently, tetrabromobisphenol A (TBBPA) is among the most utilized flame retardants in the industry globally [4,5], which is classified as an endocrine disruptor. Endocrine disruptors are chemical compounds which inhibit the activities of natural hormones in the body, such as secretion, binding, transport, synthesis, action, or elimination responsible for maintaining reproduction, homeostasis, behavior, or development. Numerous concerns have been raised about human exposure to these disruptors, primarily because of the assumed detrimental effect they pose to human health [1,6,7].
Owing to the high volume of production and potential human exposures, the toxicity of TBBPA has been investigated in a number of experimental studies. Research carried out on TBBPA has revealed less than 4% of its particles in dust are respirable and less than 10 µm can be absorbed from the lungs for systemic circulation after inhalation [8]. However, based on the physicochemical properties of TBBPA, its absorption via dermal exposure is expected to be poor. Data from an in vitro study, conducted with human skin, showed that less than 1% of the administered dose was absorbed dermally [9]. Human samples and rat strains have been studied for the metabolism and toxicokinetic action of TBBPA, which has confirmed that TBBPA can be absorbed from the gastrointestinal tract and rapidly eliminated after conjugation or Phase II metabolism to more water-soluble metabolites [10]. TBBPA has low (F < 0.05) systemic bioavailability due to its extensive hepatic bio-transformation to glucuronides and sulfates, which are excreted from the liver predominantly with bile as a result of their high molecular weight. Knudsen’s group [11] observed in their study that excretion was delayed only after a single dose of 1000 mg/kg bw, was orally administered, obviously because of the saturation of conjugation reactions. Other studies, showed that more than 95% of TBBPA administered orally is partially excreted as the parent compound and in feces it is eliminated in the form of metabolites within 3 days after a single dose with accompanying minute tissue retention or bioaccumulation, even at lower doses [11,12]. ln human plasma, the expected half-life of TBBPA-glucuronide is estimated to be between 2 and 3 days [13].
- Tetrabromobisphenol A
- oxidative stress
- genotoxicity
- neurotoxicity
Mechanism of Action of TBBPA
Effects of TBBPA on Immunosuppression and Inflammation
Current findings on the health implications of TBBPA have revealed the possibility of endocrine disruption and neurological toxicity [1,85,101]. Due to the fact that humans are exposed via inhalation of dust/air, the respiratory system could be susceptible to TBBPA. In addition, little is known about its impact on the immune and respiratory systems. Koike et al. [80] observed that exposure to TBBPA could not increase the expression of interleukin-8 (IL-8) but rather interleukin-6 (IL-6) and intercellular adhesion molecule-1(ICAM-1). TBBPA stimulated the epidermal growth factor (EGF) production and phosphorylation of the epidermal growth factor receptor (EGFR). Inhibitors of the mitogen-activated protein kinase and EGFR-selective tyrosine kinase obstructed the increasing expression of proinflammatory proteins. Additionally, they studied the modulation for nuclear receptors which revealed ligand activity for thyroid hormone antagonist and thyroid hormone receptor suppressed the increase of the expression of IL-6 and ICAM-1 significantly. They concluded that in bronchial epithelial cells the expression of proinflammatory proteins can be obstructed by TBBPA, through either the variation of nuclear receptors or EGFR-related pathways. Another study was conducted to examine whether TBBPA activates inflammatory pathways, particularly the production of prostaglandins and cytokines, in the first trimester placental cell line HTR-8/SVneo in humans. The lowest concentration of TBBPA enhanced the release of IL-8, IL-6, and prostaglandin E2 (PGE2). It also suppressed the release of TGF-β in HTR-8/SVneo cells [79].
Furthermore, human natural killer lymphocytes have the potential to damage tumor cells and cells that are virally infected. TBBPA exposure as an environmental hazard had a noticeable effect on NK cells’ tumor-destroying (lytic) function as well as their ability to bond to target cells, leading to the interference with NK cell lytic function [102]. TBBPA exposure reduced the production of tumor necrosis factor-alpha (TNF-α) in all immune cells, irrespective of their composition [78], and also influenced the lytic activity of the NK cell by reducing NK cells’ potential to bond to targeted cells [102].
TBBPA treatment significantly increased the expression of matrix metalloproteinase-9 (MMP-9) and its promoter activity in human breast cancer MCF-7 cells. Transient transfection with MMP-9 mutant promoter constructs established that TBBPA’s effects are mediated by nuclear factor-kappaB (NF-κB) and activator protein-1 (AP-1) response elements. Additionally, the expression of TBBPA-triggered MMP-9 was facilitated by activation of the AP-1 and NF-κB transcription owing to the phosphorylation of mitogen-activated protein kinase (MAPK) and Akt signaling pathways. Furthermore, a particular NADPH oxidase inhibitor and a ROS scavenger inhibited TBBPA-stimulated activation of the MAPK/Akt pathways and MMP-9 expression. Findings from this study indicate that TBBPA could promote cancer cell metastasis in MCF-7 cells via the release of MMP-9 via ROS-dependent MAPK and Akt pathways [103].
Oxidative Stress
After entering the body, TBBPA could hinder cell function and affect human health adversely by acting as a thyroid hormone. To date, our understanding on the possible health effects of TBBPA on humans is restricted to results of in vitro assays. ROS have been determined in a variety of human cells, including lung cancer cells, immune cells, normal cells and using in vitro assays. TBBPA was found to increase ROS production in each case. In addition, TBBPA induced ROS in human neutrophil granulocytes in a concentration-dependent manner [32]. Choi et al. [100] argued in their research that TBBPA also reduced ATP levels, resulting in necrosis or apoptosis as well as a decrease in the release of cyclophilin A and B. TBBPA also boosted malondialdehyde (MDA) levels in human airway epithelial cells (A549), ROS production, and caspase-3 activity. However, cells were found to have dilated smooth endoplasmic reticulum and severely damaged the mitochondria after high levels of TBBPA exposure [72]. The nuclear receptor peroxisome proliferator-activated receptor γ (PPAR γ) has demonstrated to be a key metabolic transcriptional controller, with roles in obesity, insulin resistance, inflammation, atherosclerosis, tumors, and control of glucose metabolism. TBBPA increased the expression of aP2, LPL, adipocyte-related mRNA in human mesenchymal stem cells via a PPARγ-dependent method. It also raised the amount of lipid droplets in the body [73]. According to Hoffmann et al. [74] TBBPA boosted epithelial ovarian cancer cell line (OVCAR-3) secretion and apelin production, which does not involve estrogen receptors but the peroxisome proliferator-activated receptor γ. Furthermore, the expression of apelin receptor was higher in epithelial cancer cells than in granulosa tumor cells, although apelin expression and secretion were the contrary.
TBBPA Induced Genotoxicity
In human peripheral blood mononuclear cells, a lower concentration of TBBPA induced DNA damage, stimulated oxidative mutilation to pyrimidines and purines [104]. A low TBBPA concentration was known to down-regulate the transmembrane transport of the cell membrane-related genes and cellular skeleton, proving that the membrane damage was genetically controlled. It has been reported that the expression of profibrotic genes and proteins were upregulated after a short-term TBBPA exposure [105].
TBBPA Induced Neurotoxicity Dysfunction
TBBPA exposure can cause neurotoxicity and interrupt the function, activity and production of some hormones (thyroid, estrogen) as well as MAPK, PPAR-related signaling pathways. These pathways control transporters of the central nervous system (CNS) barriers. Cannon and co-workers [106] observed in their study that TBBPA induced permeability variations in the blood brain barrier, by altering brain homeostasis, obstructing CNS drug delivery, and increasing the brain’s exposure to this chemical compound. Another study showed that TBBPA affected the development of neural ectoderm, which impacted neuron transmission, axon growth and dysregulated the signaling pathways of wingless-related integration site (WNT) and aryl hydrocarbon receptor (AHR) in human embryonic stem cells [98]. TBBPA can potentially affect the expression of human neural stem cell identity and neurogenesis by competing with NOTCH, GSK3β, and T3 signaling [107]. Levels of the presynaptic protein SNAP-25 could be increased by TBBPA exposure. This plays a significant role in exocytosis and intracellular vesicular transport, which is related to cognitive abilities and hyperactivity in some neuropsychiatric conditions [108].
This entry is adapted from the peer-reviewed paper 10.3390/molecules28062505
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