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Podophyllotoxin induces testicular toxicity via the microbiota-gut-testis axis based on the toxicological evidence

Yuanyang Shao1, Yu Wang2, Yihang Dai3

  • 1Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.

The Journal of Steroid Biochemistry and Molecular Biology
|July 24, 2026
PubMed

Insights

Podophyllotoxin (PPT) causes testicular toxicity in male rats by disrupting the gut microbiota and vitamin B6 metabolism. This natural lignan impacts sperm quality and hormone levels, highlighting the microbiota-gut-testis axis in its adverse effects.

Area of Science:

  • Toxicology
  • Reproductive Biology
  • Microbiome Research

Background:

  • Podophyllotoxin (PPT) is a natural lignan known for antitumor properties but also ovarian toxicity.
  • Potential testicular toxicity of PPT in males remains under-investigated.
  • The Toxicological Evidence Chain (TEC) framework guides systematic toxicity assessment.

Purpose of the Study:

  • To investigate the potential testicular toxicity of Podophyllotoxin (PPT) in male Sprague-Dawley rats.
  • To elucidate the mechanisms underlying PPT-induced testicular injury.
  • To explore the role of the microbiota-gut-testis (MGT) axis in PPT toxicity.

Main Methods:

  • Integrated approach: physiological/pathological phenotyping, metabolomics (intestinal, serum, testicular), transcriptomics, and gut microbiota 16S rDNA sequencing.
  • Oral administration of PPT (20 mg/kg/day for 4 days) to male rats.
  • Analysis of systemic, colonic, and testicular parameters, including hormone levels, sperm quality, and gene expression.

Main Results:

  • PPT induced systemic toxicity (weight loss, hemorrhage, diarrhea) and significant testicular damage (reduced weight, histopathology, impaired sperm quality).
  • Suppressed serum levels of testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were observed.
  • Colonic injury and gut dysbiosis (reduced Lactobacillus, increased Proteus/Escherichia-Shigella) were linked to disrupted vitamin B6 metabolism and suppressed steroidogenic gene expression.

Conclusions:

  • Podophyllotoxin (PPT) induces testicular injury in male rats.
  • The microbiota-gut-testis (MGT) axis, involving gut dysbiosis and altered vitamin B6 metabolism, plays a crucial role in PPT-induced testicular toxicity.
  • Findings highlight the need to consider MGT axis interactions in the toxicological assessment of PPT.
Keywords:
Gut microbiotaMetabolomeMicrobiota-gut-testis axisPodophyllotoxinTesticulotoxicityToxicological evidence chain

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