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<p>Methoxyacetic acid (MAA) is a testicular toxin that targets spermatocytes and round spermatids by disrupting mitochondrial function, leading to cellular energy depletion. Male Sprague-Dawley rats were given single oral doses of MAA (150 or 650&#xa0;mg/kg), resulting in no mortality but transient toxicity signs and modest body weight effects, especially at the higher dose. Histopathology revealed dose- and time-dependent testicular damage, with selective germ cell necrosis by 48&#xa0;h and extensive germ cell loss, spermatic giant cells, and epididymal inflammation observed in high-dose animals by 168&#xa0;h. Metabolic analysis using high resolution <sup>1</sup>H NMR spectroscopy and OPLS-DA identified elevated urinary excretion of <i>N</i>-butyryl glycine, a marker of mitochondrial dysfunction and impaired β-oxidation. The persistence of <i>N</i>-butyryl glycine and altered energy metabolites up to 168&#xa0;h indicates sustained mitochondrial stress and disruption of ATP-dependent processes essential for spermatogenesis. Moreover, the close structural similarity between MAA and butyrate raises the possibility that MAA interacts directly with enzymes involved in butyryl-CoA turnover during the terminal steps of β-oxidation in rodents.</p>

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Methoxyacetic acid exposure in rats induces N-butyrylglycinuria consistent with beta-oxidation impairment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • Samuele Sala,
  • Janonna Kadyrov,
  • Andres Bernal,
  • Andres M. Castillo,
  • Preechaya Naraprasertkul,
  • Nadia Paesalasakul,
  • Proud Bekanan,
  • Issariya Dhitsuwon,
  • Thanaporn Kulthawatsiri,
  • Reika Masuda,
  • Manthan Sharma,
  • Jutarop Phetcharaburanin,
  • Bruce D. Car,
  • Jose Ivan Serrano Contreras,
  • John C. Lindon,
  • Julien Wist,
  • Jeremy K. Nicholson,
  • Elaine Holmes

摘要

Methoxyacetic acid (MAA) is a testicular toxin that targets spermatocytes and round spermatids by disrupting mitochondrial function, leading to cellular energy depletion. Male Sprague-Dawley rats were given single oral doses of MAA (150 or 650 mg/kg), resulting in no mortality but transient toxicity signs and modest body weight effects, especially at the higher dose. Histopathology revealed dose- and time-dependent testicular damage, with selective germ cell necrosis by 48 h and extensive germ cell loss, spermatic giant cells, and epididymal inflammation observed in high-dose animals by 168 h. Metabolic analysis using high resolution 1H NMR spectroscopy and OPLS-DA identified elevated urinary excretion of N-butyryl glycine, a marker of mitochondrial dysfunction and impaired β-oxidation. The persistence of N-butyryl glycine and altered energy metabolites up to 168 h indicates sustained mitochondrial stress and disruption of ATP-dependent processes essential for spermatogenesis. Moreover, the close structural similarity between MAA and butyrate raises the possibility that MAA interacts directly with enzymes involved in butyryl-CoA turnover during the terminal steps of β-oxidation in rodents.