DBDPE-induced inhibition of mitochondrial complex Ⅰ leading to population decline via neurotoxicity and metabotoxicity.

Lihua Yang, Biran Zhu, Yumiao Sun, Tao Xu, Jian Han and Bingsheng Zhou

The stressor DBDPE, used as a substitute for PBDEs, has widespread industrial applications. When zebrafish (Danio rerio) were cultured in water with high concentrations of DBDPE (100nM), multigenerational and transgenerational effects were observed in subsequent generations which increase malformation rate and decrease the survival rate. When nicotinamide riboside (NR) was added to the culture water, the adverse effects of DBDPE was alleviated (Yang et al., 2023). This intervention led us to determine that the disruption of regeneration of NAD⁺, which indicates the inhibition of mitochondria complex Ⅰ, serves as the molecular initiating event, triggering a series of downstream key events.

The molecular initiating event, inhibition of mitochondrial complex Ⅰ induces disruption of redox homeostasis, then disrupts the mitochondrial electron transport chain (Karamanlidis et al., 2013; Titov et al., 2016), leading to decreased ATP production(Vartak, Porras and Bai, 2013; Yang et al., 2023), following disrupts glucolipids metabolism (Gao et al., 2022; Vendemiale et al., 2001; Wang et al., 2014). Also, ATP production disrupts affecting neurotransmitter release(Harris, Jolivet and Attwell, 2012), resulting in the larvae behavior abnormality(Cavalcante et al., 2017; Ji et al., 2022; Yu et al., 2022). Finally, the impact of glucolipids metabolism and abnormal behavior in zebrafish larvae impairs larval development(Langer-Jaesrich, Kienle, Köhler and Gerhardt, 2010; Lu et al., 2019; Wu et al., 2021), then increasing the occurrence of malformations, which ultimately increasing mortality rates of larvae. The culmination of these effects is an overall decline in population growth rate, representing the adverse outcome of disruption of redox homeostasis.

Decabromodiphenyl ethane (DBDPE) is a novel brominated flame retardant that is becoming increasingly prevalent in environmental and biota samples. As the molecular mechanism of its effects on living organisms remains unclear, this AOP is developed for its toxicity from the molecular level to the population level.

In this study, zebrafish embryos were exposed to DBDPE until 120 hours post fertilization (hpf) to assess its toxicity. Behavioral tests, neurotransmitter analysis, and transcriptome investigations on neurodevelopment-related genes revealed the neurotoxicity of DBDPE. Metabolomics analysis focusing on glycolipid metabolism, oxidative phosphorylation, and oxidative stress were conducted to validate metabolism alterations. The mitochondrial performance was evaluated by mitochondrial oxidative respiration tests including mitochondrial respiratory chain complex activities, mitochondrial membrane potential, and ATP contents, which demonstrated inhibited mitochondrial function. Furthermore, the addition of nicotinamide riboside was found to restore the impairments caused by DBDPE on mitochondria and neurons, indicating the molecular initiating event underlying its toxicity.

This AOP is developed for zebrafish embryos exposed up to 120 hpf at the larval stage without a specific gender. It provides novel insight into the toxic mechanisms of DBDPE as well as other emerging pollutants.

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