Multi-omics analysis reveals that iron deficiency impairs spermatogenesis by gut-hormone synthesis axis

Zhang, Fa‐Li; Yuan, Shuai; Dong, Pei-Yu; Ma, Hao-Hai; Felici, Massimo De; Shen, Wei; Zhang, Xifeng

doi:10.1016/j.ecoenv.2022.114344

Cited by 15 publications

(5 citation statements)

References 41 publications

(53 reference statements)

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“…Various trace elements in the body can cause abnormalities in sperm. Abnormal gut microbiota and hormone synthesis caused by iron de ciency can indirectly impair spermatogenesis [15] . At the same time, sperm motility needs to increase the concentration of intracellular calcium ions [16] .…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota and male fertility: a two-sample Mendelian randomization study

Kang,

Wang

2023

Preprint

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Background Previous studies have reported that alterations in gut microbiota composition are associated with male fertility. However, it is unclear and difficult to establish whether these associations reflect a causal relationship. Objective To reveal the causal association between gut microbiota and male fertility, we conducted a two-sample Mendelian randomization (MR) analysis. Materials and Methods We assessed genome-wide association study (GWAS) summary statistics for gut microbiota and male fertility to perform MR analysis. Independent single nucleotide polymorphisms closely associated with 211 gut bacterial taxa (N = 122110) were identified as instrumental variables. The summary statistic data for male infertility (N = 733,479), abnormal spermatoz (N = 209,921) and erectile dysfunction (N = 223,805) were obtained from the latest release from the FinnGen consortium as the outcome of interest. Two-sample MR was performed to evaluate the causal effect of gut microbiota on male fertility, including inverse-variance-weighted (IVW) method, weighted median method, MR-Egger, mode-based estimation and MR-PRESSO. A series of sensitivity analyses was performed to validate the robustness of the results. The robustness of the estimation was tested by a series of sensitivity analyses including Cochran’s Q test, MR-Egger intercept analysis, leave-one-out analysis and funnel plot were used to assess the causal association. Results Combining the results from the discovery and replication stages, we identified three causal bacterial genus. Ruminiclostridm6 (OR = 0.537, 95%CI = 0.292-0.987, P = 0.045, PFDR = 0.234) was found to be closely associated with male infertility, and the decrease in its quantity increased the risk of male infertility. Decreased Prevotella9 (OR = 0.670, 95%CI = 0.452-0.992, P = 0.046, PFDR = 0.175) was found to be closely related to abnormal sperm. Lachnospiraceae NC2004 group (OR = 1.173, 95%CI = 1.008-1.366, P = 0.078, PFDR = 0.530) was found to be closely related to male erectile dysfunction, and there was a positive correlation between them. No heterogeneity and pleiotropy were detected. Conclusion This study implied a causal relationship between the Ruminiclostridm6 genus, Prevotella9 genus, Lachnospiraceae NC2004 group genus and male fertility, thus providing novel insights into the gut microbiota-mediated development mechanism of ADs. Nevertheless, future studies are warranted to dissect the underlying mechanisms of specific bacterial taxa’s role in the pathophysiology of male fertility.

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Section: Discussionmentioning

confidence: 99%

Gut microbiota and male fertility: a two-sample Mendelian randomization study

Kang,

Wang

2023

Preprint

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“…In ammation reduces the number of Leydig cells and spermatozoa, decreases sperm viability and affects the synthesis of testicular steroid hormones [42,43]. In addition to altering the microbiota, iron de ciency interferes with the expression of genes involved in spermatogenic activity, resulting in impairment of male reproductive function [44]. Iron de ciency also increases oxidative stress in the testes, and iron supplementation can mitigate oxidative damage and repair testicular dysfunction [45].…”

Section: Discussionmentioning

confidence: 99%

High-fat diet impairs male fertility by disrupting Divalent metal transporter 1 and miR-135b in the gut-testis axis

Zhang

et al. 2023

Preprint

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Background Obese patients have been found to be susceptible to iron deficiency, and malabsorption of dietary iron is the cause of obesity-related iron deficiency (ORID). Divalent metal transporter 1 (DMT1) and ferroportin (FPN), are two transmembrane transporter proteins expressed in the duodenum that are closely associated with iron absorption. However, there have been few studies on the association between these two proteins and the increased susceptibility to iron deficiency in obese patients. Chronic inflammation is also thought to be a cause of obesity-related iron deficiency, and both conditions can have an impact on spermatogenesis and impair male reproductive function. Based on previous studies, transgenerational epigenetic inheritance through gametes was observed in obesity. Results Our results showed that obese mice had decreased blood iron levels (p < 0.01), lower protein and mRNA expression for duodenal DMT1 (p < 0.05), but no statistically significant variation in mRNA expression for duodenal FPN (p > 0.05); there was an increase in sperm miR-135b expression (p < 0.05). Bioinformatics revealed ninety overlapping genes and further analysis showed that they were primarily responsible for epithelial cilium movement, fatty acid beta-oxidation, protein dephosphorylation, fertilization and glutamine transport, which are closely related to spermatogenesis, sperm development and sperm viability in mice. Conclusions In conclusion, this study demonstrated that high-fat diet impairs male fertility by disrupting DMT1 and miR-135b in the gut-testis axis.

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“…Of note, amplification was performed in 20 μL reactions according to manufacturer’s instructions. The amplification conditions of PCR were as follows: the reaction was initialed at 95 °C for 5 min, followed by 40 cycles of denaturing at 95 °C for 10 s, annealing at 60 °C for 34 s and extension at 72 °C for 20 s. The 2-△△Ct method was used to calculate the relative gene expression to β-actin [ 36 , 37 ]. The primer sequence is detailed in Table S3 .…”

Section: Methodsmentioning

confidence: 99%

Aging-related aneuploidy is associated with mitochondrial imbalance and failure of spindle assembly

Zhang

Zhu

et al. 2023

Cell Death Discov.

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Despite aging is closely linked to increased aneuploidy in the oocytes, the mechanism of how aging affects aneuploidy remains largely elusive. Here, we applied single-cell parallel methylation and transcriptome sequencing (scM&T-seq) data from the aging mouse oocyte model to decode the genomic landscape of oocyte aging. We found a decline in oocyte quality in aging mice, as manifested by a significantly lower rate of first polar body exclusion (P < 0.05), and dramatically increasing aneuploidy rate (P < 0.01). Simultaneously, scM&T data suggested that a large number of differential expression genes (DEGs) and differential methylation regions (DMRs) were obtained. Next, we identified strong association of spindle assembly and mitochondrial transmembrane transport during oocyte aging. Moreover, we verified the DEGs related to spindle assembly (such as Naip1, Aspm, Racgap1, Zfp207) by real-time quantitative PCR (RT-qPCR) and checked the mitochondrial dysfunction by JC-1 staining. Pearson correlation analysis found that receptors for mitochondrial function were strongly positively correlated with abnormal spindle assembly (P < 0.05). In conclusion, these results suggested that the mitochondrial dysfunction and abnormal spindle assembly of aging oocytes ultimately may lead to increased oocyte aneuploidy.

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Multi-omics analysis reveals that iron deficiency impairs spermatogenesis by gut-hormone synthesis axis

Cited by 15 publications

References 41 publications

Gut microbiota and male fertility: a two-sample Mendelian randomization study

Gut microbiota and male fertility: a two-sample Mendelian randomization study

High-fat diet impairs male fertility by disrupting Divalent metal transporter 1 and miR-135b in the gut-testis axis

Aging-related aneuploidy is associated with mitochondrial imbalance and failure of spindle assembly

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