Nolasco-Pérez Teresita de Jesús, Salazar-Castañón Víctor Hugo, Cervantes-Candelas Luis Antonio, Buendía-González Fidel Orlando, Aguilar-Castro Jesús, Legorreta-Herrera Martha
Laboratorio de Inmunología Molecular, Unidad de Investigación Química Computacional, Síntesis y Farmacología en Moléculas de Interés Biológico, División de Estudios de Posgrado e Investigación, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 09320, CP, Mexico.
Posgrado en Ciencias Biológicas, Unidad de Posgrado, Universidad Nacional Autónoma de México, Circuito de Posgrados, Ciudad Universitaria, Ciudad de México 04510, CP, Mexico.
Int J Mol Sci. 2025 Apr 20;26(8):3898. doi: 10.3390/ijms26083898.
Malaria, the deadliest parasitic disease in the world, is sexually dimorphic, inflammatory, and oxidative. Males experience more severe symptoms and mortality than females do; therefore, the roles of 17β-estradiol and testosterone in this phenomenon have been studied. Both hormones affect oxidative stress, the primary mechanism of elimination. Estradiol has antioxidant activity, but the role of testosterone is controversial. Testosterone increases oxidative stress by reducing superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities, which increase lipoperoxidation in the testis. However, the antioxidant properties of testosterone in prostate and nervous tissue have also been reported. The discrepancies are probably because when testosterone levels increase, the aromatase enzyme transforms testosterone into estrogens that possess antioxidant activity, which masks the results. Therefore, it is unknown whether testosterone is involved in the sexual dimorphism that occurs in oxidative stress in malaria. In this work, we administered testosterone and simultaneously inhibited aromatase with letrozole to evaluate the role of testosterone in the sexually dimorphic pattern of oxidative stress that occurs in the blood, spleen, and brain of male and female CBA/Ca mice infected with ANKA ( ANKA). Testosterone triggers parasitemia in males, who also display more oxidative stress than females in the absence of infection, leading to sexually dimorphic patterns. Interestingly, increasing testosterone levels in infected mice reduced oxidative stress in males and increased oxidative stress in females, reversing or eliminating the dimorphic patterns observed. Oxidative stress varies in each tissue; the brain was the most protected, while the blood was the greatest damaged. Our findings highlight the role of testosterone as a regulator of oxidative stress in a tissue and sex-specific manner; therefore, understanding the role of testosterone in malaria may contribute to the development of sex-specific personalized antimalarial therapies.
疟疾是世界上最致命的寄生虫病，具有性别二态性、炎症性和氧化性。男性比女性经历更严重的症状和更高的死亡率；因此，人们对17β-雌二醇和睾酮在这一现象中的作用进行了研究。这两种激素都会影响氧化应激，而氧化应激是清除病原体的主要机制。雌二醇具有抗氧化活性，但睾酮的作用存在争议。睾酮通过降低超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）和过氧化氢酶（CAT）的活性来增加氧化应激，从而增加睾丸中的脂质过氧化。然而，也有报道称睾酮在前列腺和神经组织中具有抗氧化特性。差异可能是因为当睾酮水平升高时，芳香化酶会将睾酮转化为具有抗氧化活性的雌激素，从而掩盖了结果。因此，尚不清楚睾酮是否参与了疟疾氧化应激中出现的性别二态性。在这项研究中，我们给小鼠注射睾酮，并同时用来曲唑抑制芳香化酶，以评估睾酮在感染ANKA（ANKA）的雄性和雌性CBA/Ca小鼠血液、脾脏和大脑中出现的氧化应激性别二态性模式中的作用。睾酮会引发雄性小鼠的寄生虫血症，在未感染的情况下，雄性小鼠也比雌性小鼠表现出更多的氧化应激，从而导致性别二态性模式。有趣的是，在感染的小鼠中提高睾酮水平会降低雄性小鼠的氧化应激，增加雌性小鼠的氧化应激，从而逆转或消除观察到的二态性模式。氧化应激在每个组织中各不相同；大脑受到的保护最大，而血液受到的损伤最大。我们的研究结果突出了睾酮以组织和性别特异性方式作为氧化应激调节剂的作用；因此，了解睾酮在疟疾中的作用可能有助于开发性别特异性的个性化抗疟疗法。
