Bi-allelic mutation in Fsip1 impairs acrosome vesicle formation and attenuates flagellogenesis in mice

Gamallat, Yaser; Fang, Xiang; Mai, Hanran; Liu, Xiaonan; Li, Hong; Zhou, Pei; Han, Dingding; Zheng, Shuxin; Liao, Caihua; Yang, Miaomiao; Li, Yan; Zuo, Liandong; Sun, Lijun; Hu, Hao; Li, Na

doi:10.1016/j.redox.2021.101969

Cited by 14 publications

(13 citation statements)

References 45 publications

(54 reference statements)

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“…Examples of peaks with a dose-respond trend across the three tertiles were FSIP1 gaining in H3K4me3 (important for acrosomal reaction and sperm flagellation; Fig. 3H) (Gamallat et al, 2021), and BRD1 losing in H3K4me3 chromatin interacting protein involved in brain development; Fig. 3I) (Severinsen et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

Exposure of Greenlandic Inuit and South African VhaVenda men to the persistent DDT metabolite is associated with an altered sperm epigenome at regions implicated in paternal epigenetic transmission and developmental disease – a cross-sectional study

Lismer

Shao

Dumargne

et al. 2022

Preprint

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BackgroundThe persistent organochlorine dichlorodiphenyltrichloroethane (DDT) is banned world-wide due to its negative health effects and persistence in the environment. It is exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT is applied, as well as in the arctic where it’s endocrine disrupting metabolite, p,p’-dichlorodiphenyldichloroethylene (p,p’-DDE) accumulates in marine mammals and fish. DDT and p,p’-DDE exposures are linked to birth defects, infertility, cancer, and neurodevelopmental delays. Of particular concern is the potential of DDT use to impact the health of generations to come. Generational effects of toxicant exposures have been described in animal models and implicated germline epigenetic factors. Similar generational effects have been shown in epidemiological studies. Although advances in understanding the molecular mechanisms mediating this epigenetic inheritance have been made, there remain major knowledge gaps in how this occurs in humans. In animal and human models, DNA methylation (DNAme) has been implicated in paternal epigenetic effects. In animal models, histone H3K4 trimethylation (H3K4me3) has been shown to be responsive to the paternal environment and linked with epigenetic transmission to the embryo. Our objectives were to define the associations between p,p’-DDE serum levels and alterations in the sperm methylome and H3K4me3 enrichment using next generation sequencing. We aimed to compare regions of epigenomic sensitivity between geographically diverse populations with different routes and levels of exposures, and to identify interactions between altered DNAme and H3K4me3 regions. The potential for p,p’-DDE to impact the health of the next generation was explored by examining the functions of the genomic regions impacted, their roles during embryo development, and in health and disease.MethodsIn the Limpopo Province of South Africa, we recruited 247 VhaVenda South African men from 12 villages that either used indoor residual spraying with DDT for malaria control or not. We selected 49 paired blood and semen samples, from men that ranged from 18 to 32 years of age (mean 25 years). Sample inclusion was based on normal sperm counts (> 15 million/ml), normal sperm DNA fragmentation index, and testing a range of p,p’-DDE exposure levels (mean 10,462.228 ± 1,792.298 ng/ml). From a total of 193 samples, 47 Greenlandic Inuit blood and semen paired samples were selected from the biobank of the INUENDO cohort. The subjects ranged from 20 to 44 years of age (mean 31 years), were born in Greenland, and all had proven fertility. Sample selection was based on obtaining a range of p,p’-DDE exposure levels (mean 870.734 ± 134.030 ng/ml). Here we determined the molecular responses at the level of the sperm epigenome to serum p,p’-DDE levels using MethylC-Capture-seq (MCC-seq) and chromatin-immunoprecipitation followed by sequencing (ChIP-seq). We identified genomic regions with altered DNA methylation (DNAme) and differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3) in sperm. We used in silico analyses to discover regions of differential methylation associated with p,p’-DDE levels that were predicted to be transmitted and persist in the embryo.ResultsAlterations in DNAme and H3K4me3 enrichment followed dose response-like trends, and we identified overlapping genomic regions with DNAme sensitivities in both populations. Altered DNAme and H3K4me3 in sperm occurred at transposable elements and regulatory regions involved in fertility, disease, development, and neurofunction. A subset of regions with altered sperm DNAme and H3K4me3 were predicted to persist in the pre-implantation embryo and were associated with embryonic gene expression.LimitationsThe samples were collected from remote areas of the world thus sample size is relatively small. The populations differed in the routes of exposure, timing of collection, mean age (mean of 25 versus 31 years of age in South African and Greenlandic populations respectively) and in the timing of p,p’-DDE measurement. Moreover, the Greenlandic Inuit men were proven fertile whereas the fertility status of the South African men was unknown. Confounding factors such as other environmental exposures and selection bias cannot be ruled out.ConclusionsThese findings suggest that in men, DDT and p,p’-DDE exposure impacts the sperm epigenome in a dose-responsive manner and may negatively impact the health of future generations through epigenetic mechanisms.

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Section: Resultsmentioning

confidence: 99%

Exposure of Greenlandic Inuit and South African VhaVenda men to the persistent DDT metabolite is associated with an altered sperm epigenome at regions implicated in paternal epigenetic transmission and developmental disease – a cross-sectional study

Lismer

Shao

Dumargne

et al. 2022

Preprint

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“…Protein-protein interaction network analysis by STRING showed that FSIP2 may be highly connected with FSIP1 and CFAP69. The protein level of IFT20 was downregulated significantly in the Fsip1 -/-mice testis and FSIP1 interacted with IFT20 involving sperm flagellum assembly [42]. Additionally, SPEF2 possible had the role in protein through the manchette towards the sperm tail interacting with IFT20 and CFAP69 [55,56].…”

Section: Discussionmentioning

confidence: 96%

“…However, no variations had been reported to cause the lengthened MS sperm in human, the similar phenotype as in FSIP2.Different from AKAP4, AKAP3, and FSIP1, FSIP2 was transcribed in late spermatocyte development [30]. Deficiencies of FSIP2 were associated with DFS, MMAF and globozoospermia [31][32][33]42]. Recurrent FSIP2 amplification had been linked to testicular germ cell tumor [63], and FSIP2 was also reported as a novel potential candidate gene for nonobstructive azoospermia [64].…”

Section: Discussionmentioning

confidence: 99%

“…Glycerol kinase 2 (Gk2)deficiency sperm showed abnormal localization of crescent-like mitochondria [39,41]. Fsip1 -/-sperm revealed abnormal accumulation of mitochondria [42]. In humans, abnormalities in spermatozoa, including shorter mid-pieces with fewer mitochondrial gyres, abnormal mitochondrial assembly, and structural defects in mitochondrial membranes, have been associated with asthenozoospermia [43][44][45].…”

Section: Introductionmentioning

confidence: 99%

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Novel FSIP2 Variants Induce Super-Length Mitochondrial Sheath and Asthenoteratozoospermia in Humans

Lv¹,

Tang²,

Yu³

et al. 2023

Int. J. Biol. Sci.

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Asthenoteratozoospermia is one of the major factors for male infertility, whereas the causes of large numbers of cases are still unknown. We identified compound heterozygous variants of FSIP2 in three unrelated individuals from a cohort of 105 patients with asthenoteratozoospermia by exome sequencing. Deleterious FSIP2 variations caused severe disassembly of the fibrous sheath and axonemal defects. Intriguingly, spermatozoa in our study manifested "super-length" mitochondrial sheaths, increased levels of the mitochondrial sheath outer membrane protein TOMM20 and decreased mitochondrial ATP consumption. Dislocation or deletion of the annulus and reduction or dislocation of the annulus protein SEPT4 were also observed. While the lengthened mitochondrial sheaths were not presented in men harboring SEPT4 variants. Furthermore, female partners of two of three men achieved successful pregnancies following intracytoplasmic sperm injection (ICSI). Overall, we presume that FSIP2 may not only serve as a structural protein of the fibrous sheath but also as an intra-flagellar transporter involving in the axonemal assembly, mitochondrial selection and the termination of mitochondrial sheath extension during spermatogenesis, and ICSI is an effective treatment for individuals with FSIP2-associated asthenoteratozoospermia.

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“…FSIP1 is a fibrous sheath-interacting protein, and knockout of Fsip1 provoked abnormal sperm head and flagellum ultrastructure, and impaired acrosome vesicle formation and flagella genesis in mice 40. Moreover, several other genes were initially reported to be relevant to MMAF, and the deleterious mutations in these genes were later found in patients with globozoospermia.…”

Section: Discussionmentioning

confidence: 99%

FSIP2plays a role in the acrosome development during spermiogenesis

Zheng

Wang

et al. 2022

J Med Genet

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BackgroundLoss-of-function mutations in FSIP2 result in multiple morphological abnormalities of the flagella in humans and mice. Intriguingly, a recent study found that FSIP2 might regulate the expression of acrosomal proteins, indicating that Fsip2 might be involved in acrosome development in mice. However, whether FSIP2 also function in acrosome biogenesis in humans is largely unknown, and the underlying mechanism of which is unexplored.ObjectiveOur objective was to reveal potential function of FSIP2 in regulating sperm acrosome formation.MethodsWe performed whole exome sequencing on four asthenoteratozoospermic patients. Western blot analysis and immunofluorescence staining were conducted to assess the protein expression of FSIP2. Proteomics approach, liquid chromatography-tandem mass spectrometry and co-immunoprecipitation were implemented to clarify the molecules in acrosome biogenesis regulated by FSIP2.ResultsBiallelic FSIP2 variants were identified in four asthenoteratozoospermic individuals. The protein expression of MUT-FSIP2 was sharply decreased or absent in vitro or in vivo. Interestingly, aside from the sperm flagellar defects, the acrosomal hypoplasia was detected in numerous sperm from the four patients. FSIP2 co-localised with peanut agglutinin in the acrosome during spermatogenesis. Moreover, FSIP2 interacted with proteins (DPY19L2, SPACA1, HSP90B1, KIAA1210, HSPA2 and CLTC) involved in acrosome biogenesis. In addition, spermatozoa from patients carrying FSIP2 mutations showed downregulated expression of DPY19L2, ZPBP, SPACA1, CCDC62, CCIN, SPINK2 and CSNK2A2.ConclusionOur findings unveil that FSIP2 might involve in sperm acrosome development, and consequently, its mutations might contribute to globozoospermia or acrosomal aplasia. We meanwhile first uncover the potential molecular mechanism of FSIP2 regulating acrosome biogenesis.

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Bi-allelic mutation in Fsip1 impairs acrosome vesicle formation and attenuates flagellogenesis in mice

Cited by 14 publications

References 45 publications

Exposure of Greenlandic Inuit and South African VhaVenda men to the persistent DDT metabolite is associated with an altered sperm epigenome at regions implicated in paternal epigenetic transmission and developmental disease – a cross-sectional study

Exposure of Greenlandic Inuit and South African VhaVenda men to the persistent DDT metabolite is associated with an altered sperm epigenome at regions implicated in paternal epigenetic transmission and developmental disease – a cross-sectional study

Novel FSIP2 Variants Induce Super-Length Mitochondrial Sheath and Asthenoteratozoospermia in Humans

FSIP2plays a role in the acrosome development during spermiogenesis

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