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DEHP induces apoptosis and oxidative stress and has been shown to have androgenic toxicity. However, the methods to combat DEHP\u2010induced testicular damage and the mechanisms involved remain to be elucidated. In the present study, we used melatonin, which has strong antioxidant properties, to intervene in prepubertal mice and mouse Leydig cells (TM3) treated with DEHP or its metabolite mono(2\u2010ethylhexyl) phthalate (MEHP). The results showed that melatonin protected against DEHP\u2010induced testicular damage in prepubertal mice, mainly by protecting against DEHP\u2010induced structural destruction of the germinal tubules and by attenuating the DEHP\u2010induced decrease in testicular organ coefficients and testosterone levels. Transcriptomic analysis found that melatonin may attenuate DEHP\u2010induced oxidative stress and apoptosis in prepubertal testes. In vitro studies further revealed that MEHP induces oxidative stress injury and increases apoptosis in TM3 cells, while melatonin reversed this damage. In vitro studies also found that MEHP exposure inhibited the expression levels of molecules related to the PI3K\/AKT signaling pathway, and melatonin reversed this change. In conclusion, these findings suggest that melatonin protects against DEHP\u2010induced prepubertal testicular injury via the PI3K\/AKT signaling pathway, and provide a theoretical basis and experimental rationale for combating male reproductive dysfunction.<\/jats:p>","DOI":"10.1002\/tox.24029","type":"journal-article","created":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T03:50:06Z","timestamp":1700279406000},"page":"952-964","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Protective effects of melatonin on <scp>DEHP<\/scp>\u2010induced apoptosis and oxidative stress in prepubertal testes via the <scp>PI3K<\/scp>\/<scp>AKT<\/scp> pathway"],"prefix":"10.1002","volume":"39","author":[{"given":"Jiadong","family":"Chen","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering  Chongqing China"},{"name":"Ministry of Education Key Laboratory 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