Tetrabromobisphenol A (2,2-bis(4-hydroxy-3,5-dibromophenyl)propane; TBBPA) is a widely used brominated flame retardant (BFR). TBBPA is used as a replacement for the polybrominated diphenylethers (PBDEs), which are persistent environmental BFRs that have documented negative effects on human health (Talsness et al.
2009; Kiciński et al.
2012). TBBPA can be utilized both as a reactive flame retardant in epoxy resin-printed circuit boards and as an additive flame retardant in a wide variety of commercial and household products, such as plastics, textiles and electronic appliances, including computers and televisions (Alaee et al.
2003; Covaci et al.
2009; de Wit et al.
2010). This versatility has resulted in a dramatic increase in TBBPA production. Several studies have shown that when this component is used as an additive in polymers, it can be easily released from the treated products (Sellstrom and Jansson
1995; Birnbaum and Staskal
2004). Despite its short half-life, TBBPA may accumulate in tissues following repeated exposure (Sjödin et al.
2003). Although many studies indicate that rats and humans quickly metabolize TBBPA due to its rapid conjugation with glucuronic acid and elimination in the bile, TBBPA has been detected in cow and human milk, serum, adipose tissue and umbilical cord serum (Thomsen et al.
2002; Johnson-Restrepo et al.
2008). In human serum samples 0.24–0.71 ng of TBBPA/g lipid were reported which is equal to 1.8–5.3 pM, using a conversion factor of 400 mg lipid/100 ml serum (Thomsen et al.
2002). Although the half-life of TBBPA is about 2 days in humans, continuous uptake of this compound may increase its concentrations and potentiate toxicological effects of TBBPA (Sjödin et al.
2003). According to toxicokinetic study of Schauer et al. (
2006), a single oral dose of 300 mg/kg TBBPA to adult humans resulted in a plasma concentration of over 100 μM within 3 h of exposure, and this level was maintained for approximately 6 h (elimination half-life of 13 h). Therefore, living organisms may be temporally exposed to even higher concentrations of TBBPA than they have been reported in plasma or urine samples. As numerous studies have demonstrated, TBBPA causes pathological changes in many organs, particularly the thyroid and liver, and it negatively affects the immune and reproductive systems (Van der Ven et al.
2008; Kibakaya et al.
2009). TBBPA also has carcinogenic properties, which means that exposure to this compound may lead to the development of numerous types of cancers (Shi et al.
2010). In addition, TBBPA accumulates in different brain regions and induces behavioral alterations (Nakajima et al.
2009; Viberg and Eriksson
2011). However, only a few studies have investigated the mechanism through which TBBPA acts. TBBPA was recently shown act as a peroxisome proliferator-activated receptor gamma (PPAR-γ) ligand in NIH3T3-L1 cells (Riu et al.
2011a).
PPAR-γ is a ligand-activated transcription factor that belongs to the nuclear receptor superfamily. It regulates the expression of genes that are related to metabolic processes and reducing inflammation. Importantly, PPAR-γ is widely expressed in the brain, where it has a crucial role in the regulation of nervous cell proliferation, differentiation, and apoptosis. PPAR-γ has a protective function in neurons. Yi et al. (
2009) showed that PPAR-γ activation confers neuroprotection through anti-inflammatory, anti-apoptotic, and anti-oxidative mechanisms. In addition, the activation of PPAR-γ receptor ameliorates neurodegenerative diseases (Kitamura et al.
1999; Heneka et al.
2000; Garrido-Gil et al.
2012). Although PPAR-γ activation reduces brain tissue damage in experimental models of brain diseases (Pereira et al.
2006; Tureyen et al.
2007; Zhao et al.
2011; Ridder and Schwaninger
2012), how PPAR-γ activity is regulated in neurons is unclear.
The aim of this study was to investigate the effect of TBBPA on the viability and apoptosis of mouse neocortical neurons at 7 days in vitro (DIV) after 6 and 24 h of exposure. To explore the mechanism of TBBPA action on neocortical cells, we studied the involvement of PPAR-γ in TBBPA-induced neurotoxicity.