Absence of neurotoxicity and lack of neurobehavioral consequences due to exposure to tetrabromobisphenol A (TBBPA) exposure in humans, animals and zebrafish

Abstract

Tetrabromobisphenol A (2,2′,6,6′-tetrabromo-4,4′-isopropylidenediphenol, CAS no. 79-94-7) (TBBPA) is an effective brominated flame retardant present in many consumer products whose effectiveness is attributable to its ability to retard flames and consequently save human lives. Toxicokinetic studies revealed that TBBPA when absorbed via the gastrointestinal tract is rapidly metabolized to glucuronide or sulfate metabolites which are rapidly eliminated by the kidney. TBBPA does not accumulate in the body and there is no evidence that the parent compound is present in the brain. Although this brominated flame retardant was detected in human breast milk and serum, there was no evidence that TBBPA reached the brain in in vivo animal studies as reflected by the absence of neuropathological, neurotoxic, or behavioral alterations indicating that the central nervous system is not a target tissue. These animal investigations were further supported by use of the larval/embryo observations that TBBPA did not produce behavioral changes in a larval/embryo zebrafish a model of chemical-induced neurotoxicity. Although some protein expressions were increased, deceased or not affected in the blood-brain barrier indicating no evidence that TBBPA entered the brain, the changes were contradictory, or gender related, and behavior was not affected supporting that this compound was not neurotoxic. Taken together, TBBPA does not appear to target the brain and is not considered as a neurotoxicant.

Phenotypically Anchored mRNA and miRNA Expression Profiling in Zebrafish Reveals Flame Retardant Chemical Toxicity Networks

“…TBBPA was the only FRC that produced widespread mRNA expression changes where the nervous system was not the primary target. This was consistent with the observation that TBBPA did not alter zebrafish behavior and that the nervous system was not a direct target of this FRC as reviewed in Kacew and Hayes (2020). Instead, TBBPA primarily impacted pathways that affect synthesis and targeting of proteins that enter the endoplasmic reticulum, as well as translation, which may explain the significant morphological defects observed.…”

Comparative Effects of Brominated Flame Retardants BDE-209, TBBPA, and HBCD on Neurotoxicity in Mice

“…The neurobehavioral effects of HBCD had also been reported, whereas the neurobehavioral effects of TBBPA were unequivocal. Kacew and Hayes (2020) suggest that TBBPA did not appear to target the brain and was not considered as a neurotoxicant . Our results showed that mice in the three BFR (BDE-209, TBBPA, and HBCD)-exposed group had shorter dwell times in the target quadrant and irregular trajectories.…”

Low Concentrations of Tetrabromobisphenol A Disrupt Notch Signaling and Intestinal Development in in Vitro and in Vivo Models

“…Extensive in vitro studies have indicated that TBBPA has various toxicities, including neurotoxicity, immunotoxicity, reproductive toxicity, and nuclear receptor-mediated disrupting activities. − A major concern regarding TBBPA is that it has the potential to affect thyroid hormone (TH) actions due to its structural resemblance to TH. , Many studies demonstrated thyroid disruption caused by TBBPA may have implications for TH-dependent development alterations in vertebrates such as Xenopus laevis , zebrafish, and so on. − However, not all in vitro results agree with in vivo findings from animal studies. For example, neurotoxicity of TBBPA was observed in several cell lines, , but most of mammal studies found no adverse effects associated with exposure to TBBPA. , Recently, Yin et al reported that TBBPA upregulated expression of Notch signaling target genes ( hes1 and hes5 ) in embryonic stem cells differentiating to neurons, suggesting Notch activation and contributing to neural differentiation . Given crucial roles of Notch signaling in vertebrate development and tissues homeostasis, this new finding warrants further studies, particularly in vivo .…”

“…For example, neurotoxicity of TBBPA was observed in several cell lines, 19,20 but most of mammal studies found no adverse effects associated with exposure to TBBPA. 21,22 Recently, Yin et al reported that TBBPA upregulated expression of Notch signaling target genes (hes1 and hes5) in embryonic stem cells differentiating to neurons, suggesting Notch activation and contributing to neural differentiation. 23 Given crucial roles of Notch signaling in vertebrate development and tissues homeostasis, this new finding warrants further studies, particularly in vivo.…”