DEVELOPMENT
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2025
·Vol. 152
·期 6
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IF 3.6
Lin Zhen,Rong Bowen,Wu Meixia,Yan Junyi,Hong Tong,Hou Linjun,Tang Xinzhe,Liu Qiang,Peng Xiaozhong,Chen Yao,Lan Fei,Tong Ming-Han
ASH2L is a core component of KMT2 complexes, crucial for H3K4 trimethylation. However, its role in spermatogenesis remains elusive. Here, we demonstrate an essential role of Ash2l for meiotic prophase but dispensable for mitosis in differentiated spermatogonia. Using a germ cell-specific Ash2l knockout mouse model, we reveal that Ash2l deficiency leads to meiotic arrest and sterility in both sexes. Ash2l -deficient spermatocytes exhibit failures in chromosomal synapsis associated with persistent DMC1 foci and γH2AX, resulting in meiocyte loss due to apoptosis. Conversely, Ash2l -deficient differentiated spermatogonia show normal development. Mechanistically, Ash2l deficiency results in a global loss of H3K4me3 in promoter regions and significantly decreases expression of thousands of genes. Among these are genes involved in epigenetic silencing pathways, such as H3K9 di-methylation, DNA methylation and piRNA pathways, that are crucial for transposon repression during meiotic prophase I progression. Supporting this, we observe that Ash2l mutant spermatocytes display ectopic expression of LINE1-ORF1P. Our findings therefore reveal the previously unappreciated role of ASH2L-dependent H3K4me3 modification in spermatogenesis and provide clues to the molecular mechanisms in epigenetic disorders underlying male infertility.
研究领域:
分子生物学
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生殖生物学
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遗传学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Cong Ma,Kaiqin Hu,Xueke Zhang,Yaru Yu,Zuying Xu,Tian Ma,Hongzhen Ruan,Yingying Zhang,Jiajia Wang,Xinyu Yue,Chunmei Liang,Huifen Xiang,Rui Guo,Yunxia Cao,Zhiming Ding
Arsenic is a pollutant that can cross the placenta; however, research on the effects of arsenic exposure during pregnancy on the fertility of female offspring is limited. To address this gap, we developed a mouse model to investigate the relationship between arsenic exposure during pregnancy and fertility in female offspring. Our fertility assessment revealed that gestational exposure to 1 mg/kg arsenic or higher (10 mg/kg) resulted in reduction in litter size, ovarian volume, and multistage-follicle number in female offspring. By assessing the in vitro developmental capacity of oocytes and zygotes, we confirmed that the reduced fertility was due not to impaired oocyte quality but rather to a reduction in oocyte quantity. Arsenic exposure impedes synapsis formation in MPI and compromises homologous recombination-mediated repair of double-strand breaks, resulting in fewer crossovers. This disruption activates the pachytene-checkpoint, hindering the progression of the MPI and resulting in the elimination of defective oocytes through p-Chk2 activation. Our study reveals for the first time the detrimental effects of arsenic exposure during pregnancy on the fertility of female offspring, underscoring the urgent need to prevent such exposure to safeguard reproductive health.
研究领域:
生殖生物学
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毒理学
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遗传学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF OBESITY
·
2025
·
IF 3.8
Zhao Ruolin,Tang Yujie,Zhang Yingbing,Liu Jinwang,Zhong Changsheng,Ji Bozhen,Song Weijia,Zhang Chengtu,Su Jianmin
Background/objective Palmitic acid (PA) is known to be elevated in the follicular fluid of women with obesity, negatively affecting female fertility. However, the mechanism by which PA exposure reduces female fertility is not fully understood, and how it can be treated requires further investigation. Methods We first established in vivo and in vitro models of mouse oocyte maturation at high concentrations of PA and determined the effects of treatment with agomelatine (Ago) which is a melatonin receptor agonist with antioxidant properties. We assessed oocyte maturation rates, spindle morphology and chromosome morphology, oxidative stress and apoptosis levels. Lastly, we examined energy levels, mitochondrial function, and mitochondrial synthesis-related protein expression levels. Results Our results showed that PA exposure disrupted spindle assembly and chromosome alignment, reduced microtubule stability, and impaired the meiotic maturation of oocytes. PA also disrupted mitochondrial function, leading to decreased ATP production, elevated Reactive Oxygen Species(ROS) levels, oxidative stress, and apoptosis. Remarkably, Ago supplementation promoted oocyte quality by restoring spindle/chromosome conformation, maintaining mitochondrial function, lowering ROS levels, and inhibiting apoptosis. Conclusions This study establishes that Ago ameliorates metabolic stress-induced oocyte deterioration through mitochondrial functional restoration, providing mechanistic insights into obesity-associated infertility. Importantly, our study identifies a potentially favorable drug for combating obesity-induced female infertility.
研究领域:
生殖生物学
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细胞生物学
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药理学
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内分泌学
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发育生物学
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PubMed
高影响因子
Communications Biology
·
2023
·Vol. 6
·期 1
·1-14
·
IF 5.9
Zhu Haixia,Wen Zongzhuang,Zhang Aizhen,Liu Dongyue,Wang Hongxiang,Cheng Yin,Yang Xing,Xiao Yu,Li Jianyuan,Sun Daqing,Wu Bin,Gao Jiangang
Spermatogenesis is an extremely complex process, and any obstruction can cause male infertility. RhoGDIα has been identified as a risk of male sterility. In this study, we generate RhoGDIα knockout mice, and find that the males have severely low fertility. The testes from RhoGDIα −/− mice are smaller than that in WT mice. The numbers of spermatogonia and spermatocytes are decreased in RhoGDIα −/− testis. Spermatogenesis is compromised, and spermatocyte meiosis is arrested at zygotene stage in RhoGDIα −/− mice. Acrosome dysplasia is also observed in sperms of the mutant mice. At the molecular level, RhoGDIα deficiency activate the LIMK/cofilin signaling pathway, inhibiting F-actin depolymerization, impairing testis and inducing low fertility in mouse. In addition, the treatment of RhoGDIα −/− mice with Rac1 inhibitor NSC23766 alleviate testis injury and improve sperm quality by inhibiting the LIMK/cofilin/F-actin pathway during spermatogenesis. Together, these findings reveal a previously unrecognized RhoGDIα/Rac1/F-actin-dependent mechanism involved in spermatogenesis and male fertility.
研究领域:
生殖生物学
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细胞生物学
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分子生物学
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PubMed
高影响因子
Anatomical Record-Advances in Integrative Anatomy and Evolutionary Biology
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2016
·Vol. 299
·期 4
·450-460
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IF 1.507
Fuyin Hou,Min Xiao,Jian Li,Devin W. Cook,Weidong Zeng,Caiqiao Zhang,Yuling Mi
Cadmium (Cd) is an environmental endocrine disruptor that has toxic effects on the female reproductive system. Here the ameliorative effect of grape seed proanthocyanidin extract (GSPE) on Cd-induced meiosis inhibition during oogenesis was explored. As compared with controls, chicken embryos exposed to Cd (3 µg/egg) displayed a changed oocyte morphology, decreased number of meiotic germ cells, and decreased expression of the meiotic marker protein γH2AX. Real time RT-PCR also revealed a significant down-regulation in the mRNA expressions of various meiosis-specific markers ( Stra8 , Spo11 , Scp3 , and Dmc1 ) together with those of Raldh2 , a retinoic acid (RA) synthetase, and of the receptors ( RARα and RARβ ). In addition, exposure to Cd increased the production of H 2 O 2 and malondialdehyde in the ovaries and caused a corresponding reduction in glutathione and superoxide dismutase. Simultaneous supplementation of GSPE (150 µg/egg) markedly alleviated the aforementioned Cd-induced embryotoxic effects by upregulating meiosis-related proteins and gene expressions and restoring the antioxidative level. Collectively, the findings provided novel insights into the underlying mechanism of Cd-induced meiosis inhibition and indicated that GSPE might potentially ameliorate related reproductive disorders. Anat Rec, 299:450–460, 2016. © 2016 Wiley Periodicals, Inc.
研究领域:
毒理学
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生殖生物学
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分子生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2023
·
IF 6.8
Rui Wang,Jingyue Chen,Zhaokang Cui,Yu Li,Qian Gao,Yilong Miao,Huili Wang,Bo Xiong
Diisononyl phthalate (DINP), a mixture of chemical compounds composed of diverse isononyl esters of phthalic acid, is commonly applied as a plasticizer to substitute for di (2-ethylhexyl) phthalate (DEHP). It has been demonstrated that DINP exposure impairs the functions of kidney and liver in animals. However, the effects and potential mechanisms of DINP exposure on the female reproduction, especially the oocyte quality are still poorly understood. Here, we discovered that DINP exposure weakened the porcine oocyte meiotic competency (78.9% vs 53.6%, P < 0.001) and fertilization ability (78.5% vs 34.1%, P < 0.0001) during in vitro maturation. Specifically, DINP exposure induced the persistent spindle assembly checkpoint (SAC) activation caused by the disorganized spindle/chromosome apparatus (spindle: 20.0% vs 83.3%, P < 0.001; chromosome: 20.0% vs 80.0%, P < 0.01) to arrest meiotic progression of oocytes at metaphase I stage. In addition, DINP exposure disturbed the dynamics of sperm binding (146.7 vs 58.6, P < 0.0001) and fusion proteins (19.5 vs 11.6, P < 0.0001) in oocytes to compromise their fertilization ability. In particular, transcriptome data uncovered that the action mechanism of DINP on the oocyte maturation was associated with oxidative phosphorylation, apoptosis and autophagy pathways. Lastly, we validated that DINP exposure resulted in the mitochondrial dysfunction (27.2 vs 19.8, P < 0.0001) and elevated levels of reactive oxygen species (ROS; 8.9 vs 19.9, P < 0.0001) to trigger the occurrence of apoptosis (7.2 vs 13.1, P < 0.0001) and protective autophagy (68.6 vs 139.3, P < 0.01). Altogether, our findings not only testify that DINP has a potentially adverse impact on the mammalian oocyte quality, but also provide a scientific reference regarding how environment pollutants act on the female germ cell development.
研究领域:
生殖生物学
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毒理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
TOXICOLOGY
·
2021
·
IF 4.221
Shu-Zi Deng,Chang-Long Xu,Zhong-Feng Xu,Li-Ying Zhou,Shu-Juan Xie,Kang-Na Wei,Yuan-Chang Jin,Zhao-Cheng Zeng,Xiang-Jun Yang,Shu-Hua Tan,Hai-Long Wang
Perfluorodecanoic acid (PFDA) is a member of the perfluoroalkyl substances, which are toxic to organic functions. Recently, it has been found in follicular fluid, seriously interfering with reproduction. Follicular fluid provides the oocyte with necessary resources during the process of oocytes maturation. However, the effects of PFDA on the oocyte need investigation. Our study evaluated the impacts of PFDA on the meiosis and development potential of mouse oocytes by exposing oocytes to PFDA in vitro at 350, 400, and 450 μM concentrations. The results showed that exposure to PFDA resulted in the first meiotic prophase arrest by obstructing the function of the maturation-promoting factor. It also induced the dysfunction of the spindle assembly checkpoint, expedited the progression of the first meiotic process, and increased the risk of aneuploidy. The oocytes treated with PFDA had a broken cytoskeleton which also contributed to meiotic maturation failure. Besides, PFDA exposure caused mitochondria defections, increased the reactive oxygen species level in oocytes, and consequently induced oocyte apoptosis. Moreover, PFDA produced epigenetic modifications in oocytes and increased the frequency of mature oocytes with declined development potential. In summary, our data indicated that PFDA disturbs the meiotic process and induces oocyte quality deterioration.
研究领域:
毒理学
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生殖生物学
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细胞生物学
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DOI
PubMed
高影响因子
TOXICOLOGY
·
2023
·
IF 4.5
Si-Cheng Zhao,Feng-Xin Qiao,Ming-Xin Sun,Yue-Cen Liu,Hai-Long Wang,Zhi-Ran Xu,Yu Liu
Cobalt is a kind of heavy metal which is widely used in petrochemical and biomedical industries. Animal studies have reported that cobalt would exert systemic toxicity, but its effects on the ovarian function in mammals, especially for oocyte quality remains unknown. In the present study, we report that cobalt chloride treatment affects ovary coefficient and follicular growth. Oocytes in cobalt chloride exposed mice exhibited a decreased development potential, with the evidence of decreased occurrence rate of germ vesicle breakdown and polar body extrusion. Besides, cobalt chloride disorganized meiotic spindle formation and movement, mechanically associated with affecting TACC3 and Ac-a-tubulin levels, and disturbing actin reorganization. In addition, cobalt chloride exposure result in mitochondrial cristae structures disappear, cluster distribution and potential depolarization. Altogether, these findings suggest that cobalt chloride impairs the ovarian follicle growth and affects oocyte development by disrupted spindle assembly and mitochondrial function.
研究领域:
生殖毒理学
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发育生物学
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细胞生物学
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产品关联
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PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2023
·
IF 13.6
Yidan Ma,Xinyi Mu,Rufei Gao,Yan Zhang,Yanqing Geng,Xuemei Chen,Xin Yin,Fangfang Li,Junlin He
Homologous recombination (HR) during early oogenesis repairs programmed double-strand breaks (DSBs) to ensure female fertility and offspring health. The exposure of fetal ovaries to endocrine disrupting chemicals (EDCs) can cause reproductive disorders in the adulthood. The EDC dibutyl phthalate (DBP) is widely distributed in flexible plastic products, leading to ubiquitous human exposure. Here, we report that maternal exposure to DBP caused gross aberrations in meiotic prophase I of fetal oocytes , including delayed progression, impaired DNA damage response, uncoupled localization of DMC1 and RAD51, and decreased HR. However, programmed DSBs were efficiently repaired. DBP exposure negatively regulated lysine crotonylation (Kcr) of MSH6. Similar meiotic defects were observed in fetal ovaries with targeted disruption of Msh6 , and mutation of K544cr of MSH6 impaired its association with Ku70, thereby promoting non-homologous end joining (NHEJ) and inhibiting HR. Unlike mature F1 females, F2 female mice exhibited premature follicular activation, precocious puberty, and anxiety-like behaviors. Therefore, DBP can influence early meiotic events, and Kcr of MSH6 may regulate preferential induction of HR or NHEJ for DNA repair during meiosis.
研究领域:
生殖生物学
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分子遗传学
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发育生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Comparative Biochemistry and Physiology D-Genomics & Proteomics
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2023
·
IF 3
Cheng Zhao,Sijin Wang,Yuxi Liu,Peng Chu,Bing Han,Xianhui Ning,Tao Wang,Shaowu Yin
Temperature is a critical factor that regulates the reproduction processes in teleost. However, the gonadal response mechanism to cold stress in fish remains largely unknown. In the present study, female zebrafish were exposed to different extents of low temperatures at 18 °C and 10 °C for 48 h. The ovarian histology was remarkably damaged after cold stress exposure. Integrated analysis of miRNA-mRNA was used to investigate the ovarian response to acute cold stress. A large number of mRNAs and miRNAs were altered by cold stress, which are involved in extensive biological processes . It is indicated that the signal transduction of MAPK and Calcium signaling pathway is highly engaged in zebrafish ovary to adapt to cold stress. The immune system was dysregulated by cold stress while the ovarian autophagy was activated. Remarkably increased gene number related to reproductive functions was identified in the cold stress at 10 °C compared to the control. The cold stress-induced dysregulated reproductive genes include star , hsd3b1 , hsd17b1 , inha , insl3 , amh , nanos1 and foxl2 . Combined with the dysregulated insulin, IGF and progesterone signaling, it is suggested that cold stress affects ovarian function in multiple aspects, including oocyte meiosis, folliculogenesis , final maturation and ovarian maintenance. On the other hand, the ovarian miRNA-mRNA regulatory network response to cold stress was also constructed. Overall, our result revealed the ovarian response to cold stress in zebrafish and provided insight into the fish adaptation mechanism to acute temperature change.
研究领域:
水生生物学
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生殖生物学
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分子生物学
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基因组学
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PubMed
高影响因子
REPRODUCTIVE TOXICOLOGY
·
2024
·
IF 3.3
Huilei Chen,Yang Liu,Yue Huang,Pin Zhang,Danli Du,Wenhua Yu,Caiyun Wu,Hongzhen Ruan,Ping Zhou,Zhiming Ding,Huifen Xiang
Bisphenol M (BPM), an alternative to bisphenol A (BPA), is commonly utilized in various industrial applications. However, BPM does not represent a safe substitute for BPA due to its detrimental effects on living beings. This research aimed to assess the influence of BPM exposure on the in vitro maturation of mouse oocytes. The findings revealed that BPM exposure had a notable impact on the germinal vesicle breakdown (GVBD) rate and polar body extrusion (PBE) rate throughout the meiotic progression of mouse oocytes, ultimately resulting in meiotic arrest. Investigations demonstrated that oocytes exposure to BPM led to continued activation of spindle assembly checkpoint. Further studies revealed that securin and cyclin B1 could not be degraded in BPM-exposed oocytes, and meiosis could not realize the transition from the MI to the AI stage. Mechanistically, BPM exposure resulted in abnormal spindle assembly and disrupted chromosome alignment of oocytes. Additionally, abnormal positioning of microtubule organizing center-associated proteins implied that MTOC may be dysfunctional. Furthermore, an elevation in the acetylation level of α-tubulin in oocytes was observed after BPM treatment, leading to decreased microtubule stability. In addition to its impact on microtubules, BPM exposure led to a reduction in the expression of the actin, signifying the disruption of actin assembly. Further research indicated a heightened incidence of DNA damage in oocytes following BPM exposure. Besides, BPM exposure induced alterations in histone modifications. The outcomes of this experiment demonstrate that BPM exposure impairs oocyte quality and inhibits meiotic maturation of mouse oocytes.
研究领域:
生殖生物学
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细胞生物学
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毒理学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2021
·
IF 6.291
Zhi Zhou,Xingzhen Ni,Zhongjie Wu,Jia Tang
The amino acid metabolism-related herbicides glufosinate and glyphosate are used worldwide and have flowed into the oceans, threatening the marine organisms. In the present study, physiological activities and transcriptomic profiles of the scleractinian coral Pocillopora damicornis and symbiotic Symbiodiniaceae were determined during a 48 h-exposure to the two herbicides with the final concentration of 10 μmol L −1 . Coral samples were collected at 0, 12, 24, and 48 h after exposure to determine symbiont density, chlorophyll content, as well as activities of superoxide dismutase (SOD), catalase (CAT), nitric oxide synthetase (NOS) and phenoloxidase (PO), and the caspase-3 levels, and the samples collected at 24 h were employed in the transcriptomic analysis. Specifically, the symbiont densities did not change significantly in response to the two herbicides, while the chlorophyll content increased significantly at 24 h post glufosinate exposure. SOD and CAT activities in the coral host increased significantly at 12 h after glufosinate and glyphosate exposure, while the activity of NOS in symbionts decreased significantly at 48 h after glufosinate exposure. Caspase-3 levels in the coral host declined significantly at 24 h after exposure to the two herbicides. In the transcriptomic analysis, glufosinate triggered the expression of genes related to the response to stimuli and immunoregulation in the coral host, and suppressed the expression of genes related to coral nitrogen-related metabolism, symbiont cell cycle, and response to nutrient levels. Furthermore, glyphosate activated the expression of genes involved in coral calcification and symbiont nutrient export and suppressed the expression of genes involved in coral meiosis and symbiont cell communication. These results suggest that although the coral-Symbiodiniaceae symbiosis is not disrupted, short-term glufosinate and glyphosate exposures alter several essential physiological processes including metabolism, calcification, and meiosis in the coral host, as well as the cell cycle and nutrient export in the symbiont. Summary Glufosinate and glyphosate herbicide exposures can disturb several essential physiological processes, including metabolism, calcification, and meiosis in the coral host as well as the cell cycle and nutrient export in the symbiont, threating the survival of scleractinian corals.
研究领域:
海洋生物学
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生态毒理学
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分子生物学
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珊瑚礁生态学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）