Alterations in the testicular lipidome after tumor irradiation and their potential modulation by long-term losartan treatment

Irradiation of the testes can have adverse effects on their structure and function, potentially leading to infertility. Medications that can show antioxidant activity, such as losartan may mitigate the irradiation-related deleterious effects. The goal of this study was to evaluate the impact of irradiation on rat testes fatty acid (FA) and lipid profiles, as well as to assess the effectiveness of losartan in mitigating radiation-induced changes over 2-and 60-days. Forty-six male Wistar rats were allocated into six groups: control (CTR2 and CTR60), irradiated (IR2 and IR60), and irradiated and treated with losartan (IRLOS2 and IRLOS60), euthanized 2- or 60-days post-irradiation to assess acute and late testicular effects. The FA and lipidome plasticity were evaluated by using gas chromatography-mass spectrometry and C18-liquid chromatography-mass spectrometry, respectively. Groups irradiated after 60-days, without and with losartan, showed a significant decrease in testicular content in FA 16:0, FA 22:6 n-3 and FA 22:5 n-6. Changes in the testicular lipidome, particularly in lipid species belonging to triacylglycerols (TG) and phospholipid classes including phosphatidylcholine (PC), lysophosphatidylcholine (Lyso-PC), phosphatidylserine (PS), and cardiolipin (CL), were observed. TG species were downregulated in irradiated testicular samples, but losartan was able to prevent the downregulation of several TG species containing polyunsaturated fatty acids in testes irradiated after 60-days. After 60-days, several PC lipid species (vinyl-ether or ether-linked), endogenous antioxidants, were significantly increased in testicular tissues exposed to irradiation and losartan. However, the effect was less pronounced in the presence of losartan, suggesting the protective effect of the drug. Conversely, PS, lyso-PC, and CL levels were reduced in irradiated testes after 60-days but losartan could not mitigate those effects. These lipidomic findings support previous morphological data indicating that losartan helps preserve testicular function, minimizing the effects of radiation.睾丸照射会对其结构与功能产生不良影响，可能引发不育。具有抗氧化活性的药物，如氯沙坦（losartan），可缓解辐射相关的有害效应。本研究旨在评估辐射对大鼠睾丸脂肪酸（fatty acid, FA）及脂质谱的影响，并评估氯沙坦在辐射后2天和60天两个时间点缓解辐射诱导变化的效果。将46只雄性Wistar大鼠分为6组：对照组（CTR2和CTR60）、辐射组（IR2和IR60）以及辐射联合氯沙坦治疗组（IRLOS2和IRLOS60），分别于辐射后2天或60天处死大鼠，以评估急性和迟发性睾丸损伤效应。分别采用气相色谱-质谱联用法（gas chromatography-mass spectrometry）和C18液相色谱-质谱联用法（C18-liquid chromatography-mass spectrometry）评估脂肪酸与脂质组的可塑性变化。辐射后60天的两组（未给药与给药氯沙坦）大鼠睾丸内脂肪酸16:0、二十二碳六烯酸（FA 22:6 n-3）以及二十二碳五烯酸（FA 22:5 n-6）的含量均显著降低。研究观察到睾丸脂质组发生改变，尤其涉及三酰甘油（triacylglycerols, TG）及磷脂类脂质物种，包括磷脂酰胆碱（phosphatidylcholine, PC）、溶血磷脂酰胆碱（lysophosphatidylcholine, Lyso-PC）、磷脂酰丝氨酸（phosphatidylserine, PS）与心磷脂（cardiolipin, CL）。辐射组大鼠睾丸的三酰甘油物种表达下调，但氯沙坦可阻止辐射后60天大鼠睾丸内多种含多不饱和脂肪酸的三酰甘油物种表达下调。辐射后60天，仅受辐射的睾丸组织中多种磷脂酰胆碱物种（乙烯醚键或醚键连接型）及内源性抗氧化剂含量显著升高；但在受辐射且经氯沙坦干预的组中，该效应则相对减弱，提示该药物具有保护作用。与之相反，辐射后60天的辐射组大鼠睾丸内磷脂酰丝氨酸、溶血磷脂酰胆碱及心磷脂水平均有所降低，但氯沙坦无法缓解此类变化。上述脂质组学研究结果与此前的形态学数据一致，表明氯沙坦有助于维持睾丸功能，减轻辐射带来的损伤效应。