2. Academic Validation
  3. Parthenolide Restores Testosterone Biosynthesis After Nanoplastic Exposure by Blocking ROS-Driven NF-κB Nuclear Translocation

Parthenolide Restores Testosterone Biosynthesis After Nanoplastic Exposure by Blocking ROS-Driven NF-κB Nuclear Translocation

  • Antioxidants (Basel). 2025 Oct 31;14(11):1315. doi: 10.3390/antiox14111315.
Peng Zhao 1 2,  Hao Yan 1 2,  Runchang Wang 1 2,  Jie Zhao 1 2,  Xiangqin Zheng 1 2,  Dinggang Li 1 2,  Xitong Guo 1 2,  Fengming Ji 1 2,  Chunlan Long 1 2,  Lianju Shen 1 2,  Guanghui Wei 1 2,  Shengde Wu 1 2
Affiliations

Affiliations

  • 1 Department of Urology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing 400014, China.
  • 2 Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing 400014, China.
PMID: 41300472 DOI: 10.3390/antiox14111315
Abstract

Nanoplastics are pervasive contaminants that adversely affect male reproductive function, yet the molecular basis of polystyrene nanoplastic (PS-NP) toxicity in immature testes and effective preventive strategies remain unclear. Here, male mice (postnatal days 22-35, PND 22-35) and TM3 Leydig cells were exposed to graded PS-NPs, followed by transcriptomic profiling to identify differentially expressed genes (DEGs). Candidate therapeutics were prioritized using Connectivity Map (CMap) analysis and molecular docking, and protein interactions were examined by co-immunoprecipitation (Co-IP). PS-NPs accumulated in immature testes, eliciting excessive Reactive Oxygen Species (ROS) and activation of NF-κB. These events coincided with the downregulation of steroidogenic Enzymes (CYP11A1 and StAR) and disruption of testicular microarchitecture. In TM3 cells, PS-NPs suppressed testosterone synthesis in a concentration-dependent manner; this effect was fully reversed by pretreatment with N-acetylcysteine (NAC) or Bay 11-7082. Co-IP demonstrated p65-steroidogenic factor-1 (SF-1) binding consistent with formation of a transcriptional repressor complex targeting steroidogenic genes. CMap and docking analyses nominated parthenolide (PTL) as a candidate inhibitor of NF-κB nuclear translocation (predicted binding affinity, -6.585 kcal/mol), and PTL mitigated PS-NP-induced impairment of testosterone synthesis in vitro. Collectively, these data indicate that PS-NPs disrupt testosterone biosynthesis in immature testes through the ROS/NF-κB/p65-SF-1 axis, while PTL emerges as a candidate small molecule to counter nanoplastic-associated reproductive toxicity. These findings underscore translational relevance and support future evaluation under chronic low-dose exposure conditions, including in vivo validation of PTL efficacy, pharmacokinetics, and safety.

Keywords

oxidative stress; parthenolide; polystyrene nanoplastics; steroidogenesis; testosterone.

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