Miltefosine induces reproductive toxicity during sperm capacitation by altering PI3K/AKT signaling pathway

IF 4.2 3区环境科学与生态学 Q2 ENVIRONMENTAL SCIENCES Environmental toxicology and pharmacology Pub Date : 2024-09-10 DOI:10.1016/j.etap.2024.104565

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Abstract

Miltefosine is the first and only drug approved for the treatment of leishmaniasis. It is also known as a PI3K/AKT signaling pathway inhibitor utilized in anti-cancer or anti-viral therapies. However, the impact of miltefosine on male fertility has not been fully understood. Therefore, this study was performed to investigate the effects of miltefosine on sperm function during capacitation. Duroc spermatozoa were exposed to 0, 2.5, 5, 10, 20, 40, and 80 μM miltefosine and induced for capacitation. Our results showed that miltefosine dramatically increased the expression of PI3K/AKT signaling pathway-associated proteins. Sperm motility, motion kinetics, capacitation, and tyrosine phosphorylation were significantly suppressed by miltefosine. However, intracellular ATP levels and cell viability were not significantly affected. Our findings suggest that miltefosine may disrupt sperm function by abnormally increasing the levels of PI3K/AKT signaling pathway-associated proteins. Therefore, the harmful effects of miltefosine on male reproduction should be considered when using this drug.

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米替福新通过改变 PI3K/AKT 信号通路诱导精子获能过程中的生殖毒性

米替福新是第一个也是唯一一个获准用于治疗利什曼病的药物。它也被称为 PI3K/AKT 信号通路抑制剂，可用于抗癌或抗病毒疗法。然而，米替福新对男性生育能力的影响尚未完全明了。因此，本研究调查了米替福新在获能过程中对精子功能的影响。将杜洛克精子暴露于 0、2.5、5、10、20、40 和 80 μM 的米替福新并诱导其获能。结果表明，米替福新能显著增加 PI3K/AKT 信号通路相关蛋白的表达。米替福新显著抑制了精子的运动、运动动力学、获能和酪氨酸磷酸化。然而，细胞内 ATP 水平和细胞活力并未受到明显影响。我们的研究结果表明，米替福新可能会通过异常增加 PI3K/AKT 信号通路相关蛋白的水平来破坏精子功能。因此，在使用这种药物时应考虑到米替福新对男性生殖的有害影响。

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来源期刊

Environmental toxicology and pharmacology 医学-毒理学

CiteScore

7.00

自引率

4.70%

发文量

185

审稿时长

34 days

期刊介绍： Environmental Toxicology and Pharmacology publishes the results of studies concerning toxic and pharmacological effects of (human and veterinary) drugs and of environmental contaminants in animals and man. Areas of special interest are: molecular mechanisms of toxicity, biotransformation and toxicokinetics (including toxicokinetic modelling), molecular, biochemical and physiological mechanisms explaining differences in sensitivity between species and individuals, the characterisation of pathophysiological models and mechanisms involved in the development of effects and the identification of biological markers that can be used to study exposure and effects in man and animals. In addition to full length papers, short communications, full-length reviews and mini-reviews, Environmental Toxicology and Pharmacology will publish in depth assessments of special problem areas. The latter publications may exceed the length of a full length paper three to fourfold. A basic requirement is that the assessments are made under the auspices of international groups of leading experts in the fields concerned. The information examined may either consist of data that were already published, or of new data that were obtained within the framework of collaborative research programmes. Provision is also made for the acceptance of minireviews on (classes of) compounds, toxicities or mechanisms, debating recent advances in rapidly developing fields that fall within the scope of the journal.