Sala S.Kadyrov J.Bernal A.Castillo A.M.Naraprasertkul P.Paesalasakul N.Bekanan P.Dhitsuwon I.Kulthawatsiri T.Masuda R.Sharma M.Phetcharaburanin J.Car B.D.Contreras J.I.S.Lindon J.C.Wist J.Nicholson J.K.Holmes E.Mahidol University2026-05-082026-05-082026-01-01Archives of Toxicology (2026)03405761https://repository.li.mahidol.ac.th/handle/123456789/116593Methoxyacetic 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.Pharmacology, Toxicology and PharmaceuticsEnvironmental ScienceArticleSCOPUS10.1007/s00204-026-04330-12-s2.0-1050375309361432073842047697