Ritonavir Has Reproductive Toxicity Depending on Disrupting PI3K/PDK1/AKT Signaling Pathway
Eun-Ju Jung, Jae-Hwan Jo, Claudine Uwamahoro, Seung-Ik Jang, Woo-Jin Lee, Ju-Mi Hwang, Jeong-Won Bae, Woo-Sung Kwon
Toxics, doi:10.3390/toxics12010073
Ritonavir (RTV) is an antiviral and a component of COVID-19 treatments. Moreover, RTV demonstrates anti-cancer effects by suppressing AKT. However, RTV has cytotoxicity and suppresses sperm functions by altering AKT activity. Although abnormal AKT activity is known for causing detrimental effects on sperm functions, how RTV alters AKT signaling in spermatozoa remains unknown. Therefore, this study aimed to investigate reproductive toxicity of RTV in spermatozoa through phosphoinositide 3-kinase/phosphoinositide-dependent protein kinase-1/protein kinase B (PI3K/PDK1/AKT) signaling. Duroc spermatozoa were treated with various concentrations of RTV, and capacitation was induced. Sperm functions (sperm motility, motion kinematics, capacitation status, and cell viability) and expression levels of tyrosine-phosphorylated proteins and PI3K/PDK1/AKT pathway-related proteins were evaluated. In the results, RTV significantly suppressed sperm motility, motion kinematics, capacitation, acrosome reactions, and cell viability. Additionally, RTV significantly increased levels of phospho-tyrosine proteins and PI3K/PDK1/AKT pathway-related proteins except for AKT and PI3K. The expression level of AKT was not significantly altered and that of PI3K was significantly decreased. These results suggest RTV may suppress sperm functions by induced alterations of PI3K/PDK1/AKT pathway through abnormally increased tyrosine phosphorylation. Therefore, we suggest people who use or prescribe RTV need to consider its male reproductive toxicity.
Toxics 2024, 12, 73 9 of 11 aberrant tyrosine phosphorylation may increase the phosphorylation of PI3K and PDK1, which may enhance AKT phosphorylation (Figure 4 ). Taken together, RTV is predicted to have reproductive toxicity by disrupting PI3K/PDK1/AKT signaling pathway. Therefore, we suggest when using or administering RTV, particular attention be given to male reproductive toxicity. The findings of this study are anticipated to support the further investigation of PI3K/PDK1/AKT signaling.
Supplementary Materials: The following supporting information can be downloaded at: https://www. mdpi.com/article/10.3390/toxics12010073/s1, Figure S1
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'abstract': '<jats:p>Ritonavir (RTV) is an antiviral and a component of COVID-19 treatments. Moreover, RTV '
'demonstrates anti-cancer effects by suppressing AKT. However, RTV has cytotoxicity and '
'suppresses sperm functions by altering AKT activity. Although abnormal AKT activity is known '
'for causing detrimental effects on sperm functions, how RTV alters AKT signaling in '
'spermatozoa remains unknown. Therefore, this study aimed to investigate reproductive toxicity '
'of RTV in spermatozoa through phosphoinositide 3-kinase/phosphoinositide-dependent protein '
'kinase-1/protein kinase B (PI3K/PDK1/AKT) signaling. Duroc spermatozoa were treated with '
'various concentrations of RTV, and capacitation was induced. Sperm functions (sperm motility, '
'motion kinematics, capacitation status, and cell viability) and expression levels of '
'tyrosine-phosphorylated proteins and PI3K/PDK1/AKT pathway-related proteins were evaluated. '
'In the results, RTV significantly suppressed sperm motility, motion kinematics, capacitation, '
'acrosome reactions, and cell viability. Additionally, RTV significantly increased levels of '
'phospho-tyrosine proteins and PI3K/PDK1/AKT pathway-related proteins except for AKT and PI3K. '
'The expression level of AKT was not significantly altered and that of PI3K was significantly '
'decreased. These results suggest RTV may suppress sperm functions by induced alterations of '
'PI3K/PDK1/AKT pathway through abnormally increased tyrosine phosphorylation. Therefore, we '
'suggest people who use or prescribe RTV need to consider its male reproductive '
'toxicity.</jats:p>',
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