Reproductive toxicity of ritonavir in male: Insight into mouse sperm capacitation

Jung, Eun-Ju; Lee, Woojin; Hwang, Ju-Mi; Bae, Jeong-Won; Kwon, Woosung

doi:10.1016/j.reprotox.2022.09.008

Cited by 9 publications

(8 citation statements)

References 32 publications

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“…This might be due to the species differences. Cell viability was significantly decreased at high concentrations (10 and 100 μM) of RTV, similar to a previous study with mouse spermatozoa ( Figure 1 D) [ 10 ]. This result indicates RTV may have cytotoxicity in sperm cells starting at 10 μM.…”

Section: Discussionsupporting

confidence: 90%

“…This result indicates RTV may have cytotoxicity in sperm cells starting at 10 μM. The results of our previous study [ 10 ] and the present study indicate RTV causes adverse effects on sperm functions.…”

Section: Discussionsupporting

confidence: 75%

“…In spermatozoa, RTV decreases motility, motion kinematics, capacitation status, acrosome reaction, and cell viability. This effect is due to abnormal tyrosine phosphorylation and AKT level [ 10 ]. However, how RTV regulates the PI3K/PDK1/AKT pathway is not yet known.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, samples were incubated with CM containing 0, 0.1, 1, 10, and 100 μM of RTV for 60 min under the condition of 37 °C and 5% CO 2 to induce capacitation [ 18 ]. The RTV concentrations were established by referring to previous studies [ 10 , 20 , 21 ].…”

Section: Methodsmentioning

confidence: 99%

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Ritonavir Has Reproductive Toxicity Depending on Disrupting PI3K/PDK1/AKT Signaling Pathway

Jung,

Jo,

Uwamahoro

et al. 2024

Toxics

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Ritonavir Has Reproductive Toxicity Depending on Disrupting PI3K/PDK1/AKT Signaling Pathway

Jung,

Jo,

Uwamahoro

et al. 2024

Toxics

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“…During this period, sperm motility and motion kinematic parameters undergo changes with hyperactivation. Sperm motility is vital for navigating the tract and penetrating barriers, such as the zona pellucida ( Jung et al, 2022 ). Furthermore, numerous studies have found a positive correlation between sperm motility and fertilization ( Bongso et al, 1989 ; Donnelly et al, 1998 ), emphasizing the sperm motility’s pivotal role in successful fertilization.…”

Section: Resultsmentioning

confidence: 99%

Correlation between Rab3A Expression and Sperm Kinematic Characteristics

Jang,

Jo,

Claudine

et al. 2024

Dev. Reprod.

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Ras-related (Rab) proteins, integral members of the monomeric G-protein family, play a pivotal role in regulating intracellular vesicular transport. These proteins contribute to male reproductive processes, specifically in acrosome formation, exocytosis, and sperm motility. Although a prior study indicated a correlation between Rab3A and sperm motility, including motion kinematic parameters such as mean dance, this association has only been explored within a limited sample size. Therefore, further verification is required to confirm the correlation between Rab3A and sperm motility parameters. In the present study, Rab3A expression, sperm motility, and motion kinematic parameters were analyzed in 150 boar spermatozoa. Additionally, correlations between Rab3A expression and sperm kinematic characteristics were evaluated statistically. The results revealed significant associations between Rab3A protein expression levels and various motion kinematic parameters. Specifically, Rab3A levels exhibited positive correlations with average path velocity ( p <0.05), mean amplitude of lateral head displacement ( p <0.05), and curvilinear velocity ( p <0.01). Consequently, it is proposed that Rab3A protein plays a crucial role in male fertility through its correlation with sperm kinematic characteristics, making it a potential marker for sperm motility-related assessments.

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

Jung,

Lee,

Bae

et al. 2024

Environmental Toxicology and Pharmacology

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Reproductive toxicity of ritonavir in male: Insight into mouse sperm capacitation

Cited by 9 publications

References 32 publications

Ritonavir Has Reproductive Toxicity Depending on Disrupting PI3K/PDK1/AKT Signaling Pathway

Ritonavir Has Reproductive Toxicity Depending on Disrupting PI3K/PDK1/AKT Signaling Pathway

Correlation between Rab3A Expression and Sperm Kinematic Characteristics

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

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