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Paternal BDE-209 exposure disrupts spermatogenesis in mouse offspring via cGAS-STING pathway activation and mitophagy
Jinglong Xue1, Junhong Xie1, Xiangyang Li1
1Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
Abstract:
Decabromodiphenyl ether (BDE-209) has been recognized for its adverse effects on the male reproductive system. The specific negative effects and underlying mechanisms through which BDE-209 impacts the reproductive function of offspring are not yet fully understood. The present study classified institute of cancer research (ICR) mice into control and BDE-209 treatment groups, administering doses of 0 and 75 mg/(kg·day), respectively. After 50 days of exposure, normal female mice were co-housed with the male mice, and their male offspring were sacrificed at 2 and 12 months of age. Paternal BDE-209 exposure reduced both sperm quantity and quality in offspring. Furthermore, exposure to BDE-209 resulted in DNA damage and the upregulation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) DNA-sensing and inflammatory signaling pathways. The activation resulted in Z-DNA binding protein 1 (ZBP1) binding to the mitochondrial antiviral signaling protein (MAVS), subsequently activating mitochondrial apoptosis in the testes. The activation of the cGAS-STING pathway inhibited mitophagy, leading to senescence in the testes of male offspring. In vitro studies indicated that the cGAS inhibitor RU320521 (RU.521) effectively reversed the cGAS-STING pathway activation, alleviated the mitophagy inhibition, and decreased apoptosis and senescence in mouse spermatocyte line GC-2spd cells treated with BDE-209. The results showed that paternal BDE-209 exposure might disrupt spermatogenesis in mouse offspring by activating the cGAS-STING pathway and inhibiting mitophagy. This study provides essential data on the toxicity of BDE-209 to male reproduction and have important scientific and practical implications for maintaining biodiversity and population health in general.
Insights
Paternal exposure to decabromodiphenyl ether (BDE-209) harms male offspring reproductive health by damaging sperm and activating inflammatory pathways. This disruption of spermatogenesis and mitophagy impacts fertility and testes health in mice.
Area of Science:
- Environmental Toxicology
- Reproductive Biology
- Molecular Signaling
Background:
- Decabromodiphenyl ether (BDE-209) is a flame retardant with known male reproductive toxicity.
- Mechanisms of BDE-209's impact on offspring reproductive function remain unclear.
Purpose of the Study:
- To investigate the effects of paternal BDE-209 exposure on male offspring reproductive system.
- To elucidate the underlying molecular mechanisms, including DNA damage and inflammatory pathways.
Main Methods:
- ICR mice were exposed to BDE-209 (75 mg/kg/day) or control (0 mg/kg/day) for 50 days.
- Male offspring were assessed at 2 and 12 months for sperm parameters, DNA damage, and testicular gene expression.
- In vitro studies used a cGAS inhibitor (RU320521) on BDE-209-treated mouse spermatocyte cells.
Main Results:
- Paternal BDE-209 exposure reduced sperm quantity and quality in offspring.
- BDE-209 induced DNA damage and upregulated the cGAS-STING pathway, leading to ZBP1-MAVS interaction, mitochondrial apoptosis, and mitophagy inhibition.
- Inhibition of mitophagy resulted in testicular senescence in male offspring.
- RU320521 treatment reversed BDE-209-induced pathway activation, apoptosis, and senescence in vitro.
Conclusions:
- Paternal BDE-209 exposure disrupts spermatogenesis in male offspring via cGAS-STING pathway activation and mitophagy inhibition.
- This study highlights BDE-209's reproductive toxicity and its implications for population health and biodiversity.
