Effects of Hydroxylated Polybrominated Diphenyl Ethers in Developing Zebrafish Are Indicative of Disruption of Oxidative Phosphorylation

Abstract

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been detected in humans and wildlife. Using in vitro models, we recently showed that OH-PBDEs disrupt oxidative phosphorylation (OXPHOS), an essential process in energy metabolism. The goal of the current study was to determine the in vivo effects of OH-PBDE reported in marine wildlife. To this end, we exposed zebrafish larvae to 17 OH-PBDEs from fertilisation to 6 days of age, and determined developmental toxicity as well as OXPHOS disruption potential with a newly developed assay of oxygen consumption in living embryos. We show here that all OH-PBDEs tested, both individually and as mixtures, resulted in a concentration-dependant delay in development in zebrafish embryos. The most potent substances were 6-OH-BDE47 and 6′-OH-BDE49 (No-Effect-Concentration: 0.1 and 0.05 µM). The first 24 h of development were the most sensitive, resulting in significant and irreversible developmental delay. All substances increased oxygen consumption, an effect indicative of OXPHOS disruption. Our results suggest that the induced developmental delay may be caused by disruption of OXPHOS. Though further studies are needed, our findings suggest that the environmental concentrations of some OH-PBDEs found in Baltic Sea wildlife in the Baltic Sea may be of toxicological concern.

An ecotoxicological view on neurotoxicity assessment

“…Different types of model systems have their own advantages and disadvantages related to multicellular complexity, ease of culture, variability between cultures, possibilities with regard to differentiation or genetic modification, species and costs. Test systems with non-mammalian test organisms [125, 126] may include ecotoxicologically relevant species, or methods to study the neurotoxicity endpoints may be modified to enable an application for other species.…”

Metabolic Consequences of Developmental Exposure to Polystyrene Nanoplastics, the Flame Retardant BDE-47 and Their Combination in Zebrafish

“…As previously discussed for PS, this may reflect higher energetic cost linked to detoxification and ROS buffering responses, as robust BDE-47 induced oxidative stress has been reported in a variety of species including (developing) zebrafish (Fernie et al, 2005;Shao et al, 2008;Tagliaferri et al, 2010;Costa et al, 2015;Usenko et al, 2015;Meng et al, 2020;Messina et al, 2020). Again, similar to described PS mode of actions, BDE-47 and its hydroxylated metabolite 6-OH BDE-47, have recently been described to decrease mitochondrial OXPHOS gene expression and ATP production and increase oxygen consumption indicative of OXPHOS disruption uncoupling in zebrafish (Legradi et al, 2017;Zhuang et al, 2020), suggesting a mitochondrial contribution to the observed increase in oxygen consumption rate. Like PS, BDE-47 exposure also increased the feeding rate.…”

Emerging environmental pollutants hydroxylated polybrominated diphenyl ethers: From analytical methods to toxicology research

“…Gene expression analysis indicates that 6‐OH‐BDE‐47 affects the procedure of oxidative phosphorylation, suggesting the embryo development hinder may be caused by the disruption of energy production (Peng et al, 2016). The potential influence of energy hemostasis is verified in zebrafish and zebrafish PAC2 cells (Legradi et al, 2014, 2017). Exposure of OH‐PBDEs can increase the consumption of oxygen, which is resulted from the disruption of oxidative phosphorylation via inhibition of electron transport chain and protonophoric uncoupling.…”

“…OH‐PBDEs may disturb thyroid and estrogen hormone hemostasis (Mercado‐Feliciano & Bigsby, 2008; Li et al, 2010), impair neural development (Poston et al, 2018), cause cell toxicity (An et al, 2011; Karpeta & Gregoraszczuk, 2017), induce neurotoxicity (Dingemans, van den Berg, & Westerink, 2011; Roberts, Bianco, & Stapleton, 2015), and transformed to more toxic compounds (Bastos, Eriksson, & Bergman, 2009). Moreover, the potential mechanisms that OH‐PBDEs generate adverse health effects have been illuminated via diverse research (Dingemans et al, 2008, 2010; Macaulay et al, 2015; Legradi et al, 2017; Marchitti et al, 2017; Marsan & Bayse, 2017).…”