Diabetes-induced male infertility: potential mechanisms and treatment options

Huang, Runchun; Chen, Jiawang; Guo, Buyu; Jiang, Chenjun; Sun, Weiming

doi:10.1186/s10020-023-00771-x

Cited by 3 publications

(1 citation statement)

References 160 publications

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“…Among the latter, diabetes mellitus (DM) is one of the most threatening due to its meaningful association with mortality and morbidity ( 14 ). DM, a chronic disease characterized by hyperglycemia consequent to insulin deficiency (type 1 diabetes, T1D) and/or insulin resistance (type 2 diabetes), is often associated with metabolic syndrome ( 15 ). Indeed DM is characterized by several manifestations, such as dyslipidemia, hypertension, oxidative stress, chronic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress.…”

Section: Introductionmentioning

confidence: 99%

Type 1 diabetes impairs the activity of rat testicular somatic and germ cells through NRF2/NLRP3 pathway-mediated oxidative stress

Venditti,

Romano,

Boccella

et al. 2024

Front. Endocrinol.

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BackgroundIt is well known that metabolic disorders, including type 1 diabetes (T1D), are often associated with reduced male fertility, mainly increasing oxidative stress and impairing the hypothalamus–pituitary–testis (HPT) axis, with consequently altered spermatogenesis and reduced sperm parameters. Herein, using a rat model of T1D obtained by treatment with streptozotocin (STZ), we analyzed several parameters of testicular activity.MethodsA total of 10 adult male Wistar rats were divided into two groups of five: control and T1D, obtained with a single intraperitoneal injection of STZ. After 3 months, the rats were anesthetized and sacrificed; one testis was stored at -80°C for biochemical analysis, and the other was fixed for histological and immunofluorescence analysis.ResultsThe data confirmed that T1D induced oxidative stress and, consequently, alterations in both testicular somatic and germ cells. This aspect was highlighted by enhanced apoptosis, altered steroidogenesis and Leydig cell maturity, and impaired spermatogenesis. In addition, the blood–testis barrier integrity was compromised, as shown by the reduced levels of structural proteins (N-cadherin, ZO-1, occludin, connexin 43, and VANGL2) and the phosphorylation status of regulative kinases (Src and FAK). Mechanistically, the dysregulation of the SIRT1/NRF2/MAPKs signaling pathways was proven, particularly the reduced nuclear translocation of NRF2, affecting its ability to induce the transcription of genes encoding for antioxidant enzymes. Finally, the stimulation of testicular inflammation and pyroptosis was also confirmed, as highlighted by the increased levels of some markers, such as NF-κB and NLRP3.ConclusionThe combined data allowed us to confirm that T1D has detrimental effects on rat testicular activity. Moreover, a better comprehension of the molecular mechanisms underlying the association between metabolic disorders and male fertility could help to identify novel targets to prevent and treat fertility disorders related to T1D.

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Section: Introductionmentioning

confidence: 99%

Type 1 diabetes impairs the activity of rat testicular somatic and germ cells through NRF2/NLRP3 pathway-mediated oxidative stress

Venditti,

Romano,

Boccella

et al. 2024

Front. Endocrinol.

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Diabetes and male fertility disorders

Graziani,

Scafa,

Grande

et al. 2024

Molecular Aspects of Medicine

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Hydrogen sulfide protects against toxicant acrolein-induced ferroptotic cell death in Sertoli cells

Mao,

Ji,

Chen

et al. 2024

Front. Pharmacol.

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Acrolein (ACR) is a ubiquitous environmental pollutant and byproduct of lipid peroxidation that has been implicated in male infertility. However, the molecular mechanisms underlying ACR-induced toxicity in Sertoli cells remain unclear. Given its role in inducing oxidative stress, we examined whether ferroptosis, an iron-dependent form of regulated cell death, could mediate ACR toxicity in Sertoli cells. We also tested if hydrogen sulfide (H2S), which has antioxidant and ACR detoxifying properties, could protect Sertoli cells from ACR-induced ferroptosis. ACR exposure decreased Sertoli cell viability, increased protein carbonylation and p38 MAPK phosphorylation, indicating oxidative injury. ACR also depleted glutathione (GSH), downregulated the cystine importer SLC7A11, increased intracellular ferrous iron (Fe2+) and lipid peroxidation, suggesting activation of ferroptosis. Consistently, the ferroptosis inhibitor deferoxamine (DFO) markedly attenuates ACR-induced cell death. Further studies revealed that ACR-induced ferroptotic changes were prevented by exogenous H2S and exaggerated by inhibition of endogenous H2S production. Furthermore, H2S also suppressed GPX4 inhibitor RSL3-induced intracellular ACR accumulation and ferroptosis. In summary, our study demonstrates that ACR induces ferroptotic cell death in Sertoli cells, which can be prevented by H2S through multiple mechanisms. Targeting the H2S pathway may represent a therapeutic strategy to mitigate ACR-induced Sertoli cell injury and preserve male fertility.

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Diabetes-induced male infertility: potential mechanisms and treatment options

Cited by 3 publications

References 160 publications

Type 1 diabetes impairs the activity of rat testicular somatic and germ cells through NRF2/NLRP3 pathway-mediated oxidative stress

Type 1 diabetes impairs the activity of rat testicular somatic and germ cells through NRF2/NLRP3 pathway-mediated oxidative stress

Diabetes and male fertility disorders

Hydrogen sulfide protects against toxicant acrolein-induced ferroptotic cell death in Sertoli cells

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