Decabromodiphenyl ether induces male reproductive toxicity by activating mitochondrial apoptotic pathway through glycolipid metabolism dysbiosis

Zhang, Yue; Li, Xiangyang; Li, Jing; Zhou, Guang‐Peng; Sang, Yujian; Gao, Leqiang; Jiang, Shuqin; Shi, Zhixiong; Ge, Wei; Sun, Zhiwei; Zhou, Xianqing

doi:10.1016/j.chemosphere.2021.131512

Cited by 16 publications

(13 citation statements)

References 48 publications

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“…Increasing evidence has suggested that both legacy and novel BFRs could cause mitochondrial damage, disrupt mitochondrial function, and activate the mitochondrial apoptosis pathway in spermatogenic cells. ,, Consistent with these findings, our immunofluorescence results demonstrated an elevated expression of the apoptosis-inducing factor (AIF) in zebrafish testes even at the lowest concentration of BTBPE exposure (Figure B,E). Previous studies have proved that the overexpression of heat shock protein 70 (HSP70) has a protective effect on AIF-induced apoptosis in the nerves of hypoxic or ischemic transgenic mice. , Therefore, the increased expression of AIF may be related to the decreased protein levels of HSP70 as indicated in the PPI network (Figure C).…”

Section: Resultssupporting

confidence: 87%

Mechanistic Insights into 1,2-bis(2,4,6-tribromophenoxy)ethane-Induced Male Reproductive Toxicity in Zebrafish

Zheng,

Wang,

Zhang

et al. 2024

Environ. Sci. Technol.

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The novel brominated flame retardant, 1,2-bis(2,4,6tribromophenoxy)ethane (BTBPE), has increasingly been detected in environmental and biota samples. However, limited information is available regarding its toxicity, especially at environmentally relevant concentrations. In the present study, adult male zebrafish were exposed to varying concentrations of BTBPE (0, 0.01, 0.1, 1, and 10 μg/L) for 28 days. The results demonstrated underperformance in mating behavior and reproductive success of male zebrafish when paired with unexposed females. Additionally, a decline in sperm quality was confirmed in BTBPE-exposed male zebrafish, characterized by decreased total motility, decreased progressive motility, and increased morphological malformations. To elucidate the underlying mechanism, an integrated proteomic and phosphoproteomic analysis was performed, revealing a predominant impact on mitochondrial functions at the protein level and a universal response across different cellular compartments at the phosphorylation level. Ultrastructural damage, increased expression of apoptosis-inducing factor, and disordered respiratory chain confirmed the involvement of mitochondrial impairment in zebrafish testes. These findings not only provide valuable insights for future evaluations of the potential risks posed by BTBPE and similar chemicals but also underscore the need for further research into the impact of mitochondrial dysfunction on reproductive health.

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Section: Resultssupporting

confidence: 87%

Mechanistic Insights into 1,2-bis(2,4,6-tribromophenoxy)ethane-Induced Male Reproductive Toxicity in Zebrafish

Zheng,

Wang,

Zhang

et al. 2024

Environ. Sci. Technol.

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“…However, the green fluorescence intensity of the whole cell decreased due to severe damage to the cell membrane. Apoptosis is mainly achieved through two signaling pathways, including the intracellular (mitochondrial-mediated) pathway and the extracellular (death receptor-mediated) pathway [ 32 ]. The two main features of the intracellular apoptotic pathway are the loss of mitochondrial membrane potential, and the release of cytochrome C. Cytochrome C is positively charged on the surface, and is usually loosely bound to cardiolipin, rich in unsaturated fatty acids, to fix the outer surface of the inner mitochondrial membrane [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

Potential Biochemical Pesticide—Synthesis of Neofuranocoumarin and Inhibition the Proliferation of Spodoptera frugiperda Cells through Activating the Mitochondrial Pathway

Shao

Zhang

Qian

et al. 2022

Toxins

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Furanocoumarins, the secondary metabolites of plants, are considered to be natural insecticides and fungicides because they prevent the invasion of plant pathogenic microorganisms and the predation of herbivorous insects. In this study, novel 2-arylfuranocoumarin derivatives were designed to synthesize by condensation, esterification, bromination, and Wittig reaction. The results showed an excellent photosensitive activity of 2-thiophenylfuranocoumarin (I34). Cell Counting Kit-8 detected that I34 could inhibit the proliferation of Spodoptera frugiperda (Sf9) cells in a time- and concentration-dependent manner under ultraviolet A (UV-A) light for 3 min. The inverted microscope revealed that cells treated with I34 swelled, the membrane was ruptured, and apoptotic bodies appeared. The flow cytometry detected that I34 could induce apoptosis of Sf9 cells, increase the level of intracellular reactive oxygen species (ROS), decrease the mitochondrial membrane potential, and block cell cycle arrest in the G2/M phase. Transmission electron microscopy detected cell mitochondrial cristae damage, matrix degradation, and mitochondrial vacuolation. Further enzyme activity detection revealed that the enzyme activities of apoptosis-related proteins caspase-3 and caspase-9 increased significantly (P < 0.05). Finally, Western blotting analysis detected that the phosphorylation level of Akt and Bad and the expression of the apoptosis inhibitor protein Bcl-XL were inhibited, cleaved-PARP and P53 were increased, and cytochrome C was released from the mitochondria into the cytoplasm. Moreover, under UV-A irradiation, I34 promoted the increase in ROS in Sf9 cells, activated the mitochondrial apoptotic signal transduction pathway, and finally, inhibited cell proliferation. Thus, novel furanocoumarins exhibit a potential application prospect as a biochemical pesticide.

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“…Male rats were exposed by gavage to 0, 5, 50 and 500 mg BDE‐209 /kg bw per day for 28 days (Zhang, Li, et al., 2021 ). There was a decrease in sperm quality and quantity at 50 and 500 mg/kg bw per day, the spermatocytes layers sparsely arranged and mature sperms in the lumen dramatically decreased; there were also vacuolation of seminiferous tubules and exfoliation of spermatogenic cells.…”

Section: Assessmentmentioning

confidence: 99%

“…Apoptosis of spermatogenic cells was also noted at these doses. The levels of glucose, triglyceride and total cholesterol in testes were negatively correlated with sperm concentration, and triglyceride and total cholesterol levels were negatively correlated with sperm motility, while positively correlated with the sperm malformation rate (Zhang, Li, et al., 2021 ). The NOAEL was 5 mg/kg bw per day.…”

Section: Assessmentmentioning

confidence: 99%

Update of the risk assessment of polybrominated diphenyl ethers (PBDEs) in food

Schrenk,

Bignami,

Bodin

et al. 2024

EFS2

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The European Commission asked EFSA to update its 2011 risk assessment on polybrominated diphenyl ethers (PBDEs) in food, focusing on 10 congeners: BDE‐28, ‐47, ‐49, ‐99, ‐100, ‐138, ‐153, ‐154, ‐183 and ‑209. The CONTAM Panel concluded that the neurodevelopmental effects on behaviour and reproductive/developmental effects are the critical effects in rodent studies. For four congeners (BDE‐47, ‐99, ‐153, ‐209) the Panel derived Reference Points, i.e. benchmark doses and corresponding lower 95% confidence limits (BMDLs), for endpoint‐specific benchmark responses. Since repeated exposure to PBDEs results in accumulation of these chemicals in the body, the Panel estimated the body burden at the BMDL in rodents, and the chronic intake that would lead to the same body burden in humans. For the remaining six congeners no studies were available to identify Reference Points. The Panel concluded that there is scientific basis for inclusion of all 10 congeners in a common assessment group and performed a combined risk assessment. The Panel concluded that the combined margin of exposure (MOET) approach was the most appropriate risk metric and applied a tiered approach to the risk characterisation. Over 84,000 analytical results for the 10 congeners in food were used to estimate the exposure across dietary surveys and age groups of the European population. The most important contributors to the chronic dietary Lower Bound exposure to PBDEs were meat and meat products and fish and seafood. Taking into account the uncertainties affecting the assessment, the Panel concluded that it is likely that current dietary exposure to PBDEs in the European population raises a health concern.

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Decabromodiphenyl ether induces male reproductive toxicity by activating mitochondrial apoptotic pathway through glycolipid metabolism dysbiosis

Cited by 16 publications

References 48 publications

Mechanistic Insights into 1,2-bis(2,4,6-tribromophenoxy)ethane-Induced Male Reproductive Toxicity in Zebrafish

Mechanistic Insights into 1,2-bis(2,4,6-tribromophenoxy)ethane-Induced Male Reproductive Toxicity in Zebrafish

Potential Biochemical Pesticide—Synthesis of Neofuranocoumarin and Inhibition the Proliferation of Spodoptera frugiperda Cells through Activating the Mitochondrial Pathway

Update of the risk assessment of polybrominated diphenyl ethers (PBDEs) in food

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