The neurotoxicity of DE‐71: effects on neural development and impairment of serotonergic signaling in zebrafish larvae

Abstract

The underlying mechanism of polybrominated diphenyl ether (PBDE)-induced neurotoxicity is still a major concern due to its ubiquitous nature and persistence. Here, zebrafish embryos (2 h postfertilization, hpf ) were exposed to different concentrations of the commercial PBDE mixture DE-71 (0-100 μg l -1 ) until 120 hpf, and the impact on neural development and serotonergic system was investigated. The in vivo results revealed significantly reduced transcription of genes involved in neurogenesis (fgf8, shha, wnt1), and contents of proteins in neuronal morphogenesis (myelin basic protein, synapsin IIa), suggesting an impairment of neural development in zebrafish embryos. Further results demonstrated a reduction of 5-hydroxytryptamine neuron and a dose-dependent decrease of whole-body serotonin levels, as well as the transcription of genes involved in serotonergic synthesis (tph1, tph2, trhr) and neurotransmission (serta/b, htr1aa/b). In addition, we predicted possible targets of PBDEs by molecular docking, and the results indicated that PBDE congeners showed high binding affinities with fibroblast growth factor 8 other than SHH and HTR1B. Taken together, this study demonstrated that PBDE exposure during embryogenesis could damage neural development and cause impairment of the serotonergic system as secondary effects in the zebrafish larvae.

Neurodevelopmental toxicity of pyrazinamide to larval zebrafish and the restoration after intoxication withdrawal

“…With PZA administration, these genes were significantly downregulated, such as gfap (Nielsen & Jørgensen, 2003) and mbp (Brösamle & Halpern, 2002) (Figure 6A). Albeit with an invariable expression of shha (Xianfeng Wang et al, 2016) and neurog1 (Ma et al, 1996) in zebrafish from the 1.5‐mM PZA group, their expression was reduced in zebrafish from 0.5‐ and 1.0‐mM groups. With a 2‐day restoration, expression of these genes returned to a normal level as compared with VHC, although an upregulation was observed for shha in 0.5‐ and 1.0‐mM groups and gfap in the 1.0‐mM group (Figure 6B).…”

Increased coiling frequency linked to apoptosis in the brain and altered thyroid signaling in zebrafish embryos (Danio rerio) exposed to the PBDE metabolite 6-OH-BDE-47

“…Another explanation relates to the reduction of 5-HT-ir neurons by 6-OH-BDE-47 observed in this study. The role of 5-HT in the induction of apoptosis (Trouche et al, 2010;Liu et al, 2013), may be important, especially since 5-HT depletion reduces 5-HT-ir neurons, resulting in neurotoxicity and behavioral disorders (Musumeci et al, 2015;Horzmann and Freeman, 2016;Wang et al, 2016;Schoofs et al, 2017). Adult zebrafish exposed to polycyclic aromatic hydrocarbons (PAHs) were depleted of 5-HT and paralleling monoamine concentrations, and they exhibited increased anxiety and disrupted memory regulation and learning (Vignet et al, 2017).…”

Human Oligodendrocytes and Myelin In Vitro to Evaluate Developmental Neurotoxicity

“…There is strong evidence demonstrating that thyroid hormone (TH) signaling is integral to myelin formation because TH is required for the regulation of OL differentiation and maturation [151][152][153][154][155][156][157]. Moreover, there is evidence that environmental chemicals that disrupt thyroid hormone function also disrupt myelin formation [158][159][160][161]. For example, the polybrominated diphenyl ether (PBDE) flame retardant BDE-99 was recently demonstrated to inhibit NPC differentiation into the OL lineage in vitro [162], and PBDE flame retardants are known thyroid hormone disruptors [163].…”

“…For example, the polybrominated diphenyl ether (PBDE) flame retardant BDE-99 was recently demonstrated to inhibit NPC differentiation into the OL lineage in vitro [162], and PBDE flame retardants are known thyroid hormone disruptors [163]. In addition, the leading commercial pentaBDE technical mixture, DE-71, which contains BDE-99 [164], has also been shown to downregulate the gene expression of myelin basic protein in exposed zebrafish embryos [158,160].…”