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BIOLOGY OF REPRODUCTION · 2025 · IF 3

SRA deficiency induces follicular dysplasia by disrupting the hypothalamic Kisspeptin-GPR54 system in mice

Jin Jing,Kou Xinhui,Wang Xinzhe,Yun Xue,Ding Yinyin,Cai Keshu,Zhai Yongning,Zhou Huifang

PurposeTo investigate how steroid receptor RNA activator (SRA) regulates follicular development in mice.MethodsSystemic SRA knockout mice were introduced. SRA expression was reinstated in the anteroventral periventricular nucleus (AVPV) of the hypothalamus using lentiviral vectors. Subsequently, the estrous cycle, serum hormone levels, follicle development, and hypothalamic kisspeptin expression in mice were assessed. Kiss1 promoter activity was tested with a fluorescent reporter system in Neuro-2a cells.ResultsSRA deficiency caused a shift to shorter metestrus and longer diestrus phases, reduced numbers of large antral and preovulatory follicles, increased formation of atretic cyst-like follicles, lowered serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2), and decreased expression of hypothalamic AVPV-kisspeptin in mice. The reinstatement of SRA expression in the AVPV nucleus normalized kisspeptin expression, hormone levels, and follicle development. In Neuro-2a cells, SRA increased Kiss1 transcription upon E2 treatment, a response that was nullified by the estrogen receptor alpha (ERα) inhibitor.ConclusionSRA enhances ERα-mediated Kiss1 transcription in the AVPV nucleus to control the kisspeptin-GPR54 system in hypothalamus, essential for regulating ovulation through the hypothalamus-pituitary-ovary axis.

CAS / MDL: 50-28-2
研究领域: 生殖生物学 · 内分泌学 · 分子生物学
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POULTRY SCIENCE · 2023 · IF 4.4

Effects of quercetin on granulosa cells from prehierarchical follicles by modulating MAPK signaling pathway in chicken

Manman Shen,Tao Li,Yuan Feng,Ping Wu,Boris Ramos Serrano,Adileidys Ruiz Barcenas,Liang Qu,Weiguo Zhao

ABSTRACT Quercetin ( Que ), widely found in a huge variety of plants, plays important roles in ovarian function. However, to data, there have been no reports about Que regulating granulosa cells ( GCs ) in prehierarchical follicles in chicken. Herein, GCs from follicles diameter from 4 to 8 mm in chicken were treated by Que in vitro culture to investigate how Que exerts its effect on follicular development. GCs treated by Que in concentrations of 10, 100, and 1,000 ng/mL were tested for cell proliferation and progesterone secretion. Eight cDNA libraries were constructed from GCs (4 samples per group) to explore transcriptome expression changes. The role of the MAPK/ERK signaling pathway was validated in this process. Treatment with 100 and 1,000 ng/mL levels of Que significantly promoted cell proliferation and progesterone secretion ( P < 0.05). RNA-seq analysis data showed that 402 and 263 differentially expressed genes ( DEGs ) were up- and down-regulated, respectively. Functional enrichment analysis that the pathways related to follicular development included biosynthesis of amino acids, MAPK signaling pathway, and calcium signaling pathway. Notably, the function exerted in GCs of the different levels of Que was associated with the suppression of the MAPK pathway. In conclusion, our results proved that low levels of Que could promote MAPK signaling pathway, but high levels of Que inhibit MAPK signaling pathway in GCs from the prehierarchical follicles, promote cell proliferation and progesterone secretion, and benefit follicle selection.

CAS / MDL: 117-39-5
研究领域: 动物科学 · 分子生物学 · 生殖生物学
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Journal of Ovarian Research · 2024 ·Vol. 17 ·期 1 ·1-12 · IF 3.8

Zinc deficiency deteriorates ovarian follicle development and function by inhibiting mitochondrial function

Liu Wen-Jiao,Li Li-Shu,Lan Meng-Fan,Shang Jian-Zhou,Zhang Jin-Xin,Xiong Wen-Jie,Lai Xin-Le,Duan Xing

Zinc (Zn) is a crucial trace element essential for human growth and development, particularly for reproductive health. Previous research has shown a decrease in serum zinc concentration with age and individuals with conditions such as polycystic ovary syndrome (PCOS) and diabetes mellitus. However, the specific effects of zinc deficiency on the female reproductive system, especially ovarian function, are not fully understood. In our study, we observed a significant reduction in the total number of follicles and mature follicles in the zinc deficiency group. This reduction correlated with decreased level of anti-Mullerian hormone (AMH) and abnormal gene expression affecting hormone secretion regulation. Furthermore, we found that zinc deficiency disrupted mitochondrial dynamics, leading to oxidative stress in the ovaries, which further inhibited autophagy and increased ovarian apoptosis. These changes ultimately resulted in the failure of germinal vesicle breakdown (GVBD) and reduced oocyte quality. Meanwhile, administration of zinc glycine effectively alleviated the oocyte meiotic arrest caused by dietary zinc deficiency. In conclusion, our findings demonstrated that dietary zinc deficiency can affect hormone secretion and follicle maturation by impairing mitochondrial function and autophagy.

研究领域: 生殖生物学 · 营养学 · 内分泌学
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JOURNAL OF INSECT PHYSIOLOGY · 2015 · IF 2.47

Pheromones affecting ovary activation and ovariole loss in the Asian honey bee Apis cerana

Ken Tan,Xiwen Liu,Sihao Dong,Chao Wang,Benjamin P. Oldroyd

The Asian hive bee Apis cerana has similar queen mandibular pheromones (QMP) to the Western honey bee Apis mellifera . However the effects of individual QMP components have never been tested to determine their effects on the reproductive physiology of A. cerana workers. We fed one queen equivalent of each of the major components of A. cerana QMP to groups of c.a. 500   day-old, caged, workers twice a day until the workers were 10   days old. Half of the cages were also provided with 10% royal jelly in the food. Workers were sampled each day and dissected to determine the number of ovarioles and the degree of ovary activation (egg development). In cages treated with 9-carbon fatty acids ovary activation was minimal, whereas the 10-carbon acids suppressed ovary activation very little. Royal jelly enhanced ovary activation, especially in cages treated with 10-carbon acids. The number of ovarioles declined with bee age, but the rate of decline was slowed by the 9-carbon acids in particular. The results show conservation of the composition and function of QMP between A. cerana and A. mellifera and support the hypothesis that QMP is an honest signal of queen fecundity rather than a chemical castrator of workers.

研究领域: 昆虫学 · 生殖生物学
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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES · 2023 · IF 3

A salting-out assisted liquid-liquid extraction method for 25 emerging pesticides in follicular fluid

Xin Wei,Liang Cao,Mingrui Zhou,Jiana Huang,Xiaoyan Liang,Nijie Li,Yanan Pan,Renli Yin,Huashou Li,Adela Jing Li

Emerging pesticides of neonicotinoids (NEOs) and “Universal Pesticides” (UPs) are a growing global concern due to their growing commercial importance and potential risks to human health. The currently available analytical methods for these pesticides in biomonitoring were usually tailored for limited number of analytes, or were time consuming and costly. In this study, an efficient and sensitive method for the analysis of 16 NEOs and nine UPs in human follicular fluid (FF) was developed by using a salting-out assisted liquid-liquid extraction (SALLE) method and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Method performance was evaluated by calibration linearity ( r  > 0.99), sensitivity at limits of quantification (0.01–0.50 ng/mL), accuracy at relative recoveries (81–117%) and precision at relative standard deviations (≤16%). The developed method was further validated by analyzing 21 human FF samples that were collected from a hospital in Guangzhou, China. Among the 25 study analytes, two NEOs and six UPs had their detection rates over 85% and medians at 0.048–0.808 ng/mL in the FF samples. Considering the well-known toxicity of these pesticides and their metabolites, it is urgent to figure out exposure profiles of study pesticides and potential reproductive risk for women. To the best of our knowledge, this study is the first to develop and apply the SALLE method in the extraction of 16 NEOs and nine UPs simultaneously in human FF.

研究领域: 环境科学 · 分析化学 · 生殖健康
✓ 已验证 DOI PubMed 高影响因子
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EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY · 2017 · IF 1.975

The potentiality of two-dimensional preantral follicle culture as an in vitro model in predicting premature ovarian failure

Ting Zhang,Ying Chen,Yang Yang,Zhonghui Wang,Qi Pan,Sichong Xu,Zuyue Sun

The purpose of this study is to identify the potential of a two-dimensional preantral follicle culture as an in vitro model of predicting premature ovarian failure . The two-dimensional preantral follicles culture method was established by cultivating preantral follicles collected from ICR F1 hybrids (aged 12–14   days) for 12   days. The preantral follicles were incubated with 0.54   mg/ml cyclophosphamide , 0.5   mg/ml busulfan , 0.12   mg/ml cisplatin , 3.12   mg/ml 4-vinylcyclohexene diepoxide, 5   mg/ml D (+) galactose , and 0.5   mg/ml hydrocortisone for 24   h at culture days 2, 6 and 11. The diameter of follicles, the cumulus-oocyte complex number and the maturity of oocytes were recorded as the parameters to detect follicular maturation induced by the culture agents. The results indicated that, except for busulfan, D (+) galactose, and hydrocortisone, such test articles could significantly decrease follicular growth ( p   <   0.05 or p   <   0.01), and induce oocyte degeneration and follicle atresia when the follicles were treated at day 2. With the exception of hydrocortisone, such agents also gradually decreased follicular development ( p   <   0.05 or p   <   0.01) when the follicles were treated at day 6. All of the test articles but hydrocortisone can interfere with the ovulation , the cumulus-oocyte complex discharge and oocyte maturation of follicles when treated at days 2, 6 and 11. It is suggested that two-dimensional preantral follicle culture could be utilized as a potential in vitro system to mimic the POF model. It may also be employed in screening potential ovarian toxic agents, reducing laboratory animal use and promoting animal welfare .

CAS / MDL: 106-87-6
研究领域: 生殖生物学 · 毒理学 · 动物模型
✓ 已验证 产品关联 DOI PubMed 高影响因子
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Cell Death Discovery · 2023 ·Vol. 9 ·期 1 ·1-11 · IF 7

A regulatory network controlling ovarian granulosa cell death

Yang Liu,Du Xing,Wang Siqi,Lin Chenggang,Li Qiqi,Li Qifa

Follicular atresia triggered by granulosa cell (GC) apoptosis severely reduces female fertility and accelerates reproductive aging. GC apoptosis is a complex process regulated by multiple factors, regulatory axes, and signaling pathways. Here, we report a novel, small regulatory network involved in GC apoptosis and follicular atresia. miR-187, a miRNA down-regulated during follicular atresia in sows, maintains TGFBR2 mRNA stability in sow GCs by directly binding to its 5’-UTR. miR-187 activates the transforming growth factor-β (TGF-β) signaling pathway and suppresses GC apoptosis via TGFBR2 activation. NORHA, a pro-apoptotic lncRNA expressed in sow GCs, inhibits TGFBR2-mediated activation of the TGF-β signaling pathway by sponging miR-187. In contrast, NORFA, a functional lncRNA associated with sow follicular atresia and GC apoptosis, enhances miR-187 and TGFBR2 expression by inhibiting NORHA and activating NFIX. Our findings define a simple regulatory network that controls GC apoptosis and follicular atresia, providing new insights into the mechanisms of GC apoptosis, follicular atresia, and female fertility.

CAS / MDL: 50-76-0
研究领域: 生殖生物学 · 分子生物学 · 内分泌学
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TOXICOLOGY · 2022 · IF 4.571

Alginic acid induces oxidative stress-mediated hormone secretion disorder, apoptosis and autophagy in mouse granulosa cells and ovaries

Jieyu Cui,Yankun Li,Wenqiang Zhang,Hongrun Qian,Zhiying Zhang,Kun Xu

Alginic acid (AA) is a kind of polysaccharide extracted from brown seaweeds and has been widely used in food industry. Certain positive effects of AA, such as anti-inflammation and anti-allergy, have been reported. Nevertheless, as a potential chemical contaminant of the environment, its impact on female reproductive system remains to be investigated. The purpose of this study is to explore the impact of AA on ovary and to investigate the further cellular mechanism. Primarily, in vitro cultured mouse ovary granulosa cells (GCs) were treated with AA at a concentration of 10μM for 24 h. The cells and supernatant were collected and subjected to further measures. The results demonstrated that after being treated with 10μM AA for 24 h the levels of estradiol and progesterone in supernatant were down-regulated. And excessive reactive oxygen species (ROS) and declined antioxidant capacity were also determined. Additionally, a large number of apoptotic bodies and autophagic vesicles were found in the experimental cells, and the mitochondria-mediated apoptotic pathway was demonstrated to play a main role in GCs apoptosis . To further investigate the effect of AA on ovary, the female ICR mice were administered with AA (10 mg/ kg bodyweight) intraperitoneally for successive 35 days, and the estrus phase was recorded simultaneously. After exposure, the ovaries and blood samples were collected for further analysis. The results revealed that the estrus period of the mice was shortened and the interestrus period was extended after being treated with AA for 35 days. At the organismal level, the numbers of antral follicles and atresia follicles increased and the levels of pro-apoptosis and autophagy-related proteins were detected upregulated after AA treatment. Taken together, both in vivo and in vitro data suggested that AA has toxicity on female reproduction by disrupting estrogen production and inducing oxidative stress , mitochondria-mediated apoptosis and autophagy. Our results provide new scientific basis and the concern for controlling the increasing use of AA.

CAS / MDL: 9005-32-7
研究领域: 生殖生物学 · 毒理学 · 细胞生物学 · 内分泌学
✓ 已验证 产品关联 DOI PubMed 高影响因子
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REPRODUCTIVE TOXICOLOGY · 2024 · IF 3.3

Sucralose triggers insulin resistance leading to follicular dysplasia in mice

Luyao Yang,Shuangshuang Wang,Jing Jin,Jiahui Wang,Wenyue Chen,Yun Xue,Liang Sheng,Yongning Zhai,Weifeng Yao

Sucralose, the extensively utilized sweetener, might lead to metabolic disorders with prolonged consumption, but it remains uncertain if sucralose has any impact on female reproductive health. We incorporated sucralose into drinking water and observed food intake, body weight, estrous cycle, follicular development, serum hormones, and insulin sensitivity of mice. The mice did not experience any changes in their food intake or body weight after consuming sucralose. However, they displayed irregularities in the estrous cycle, marked by a reduced count of primordial, primary, and secondary follicles, coupled with a significant increase in the number of antral follicles. There was a decline in follicle-stimulating hormone (FSH), estradiol (E2), and progesterone (P4) levels, while testosterone (T) and luteinizing hormone (LH) levels surged, leading to a notable elevation in the LH / FSH ratio. Sucralose also induced insulin resistance, as evidenced by elevated insulin levels and impaired insulin tolerance, which responded to an increase in bacterial-derived serum endotoxin. By eliminating insulin resistance with rosiglitazone (RSG), eradicating intestinal flora-derived endotoxins with neomycin (NEO), or enhancing intestinal barrier function with indole-3-carbinol (I3C), the abnormalities in estrous cycle, disruptions in follicular development, hormonal imbalances and elevation in serum endotoxins induced by sucralose were successfully reversed. The present study indicates that sucralose-induced follicular dysplasia in mice is probably related to impaired intestinal permeability, infiltration of endotoxins, initiation of systemic inflammation, and insulin resistance.

研究领域: 生殖生物学 · 内分泌学 · 微生物学
✓ 已验证 产品关联 DOI PubMed 高影响因子
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TOXICOLOGY LETTERS · 2025 · IF 2.9

Iodoacetamide triggers ovarian dysfunction in mice through TGF-β signaling pathway and apoptosis

Chenyu Xiao,Qianru Li,Meiqi Li,Yongshu Han,Hubin Xu,Haimin Jiang,Suer Zhang,Zhen Jin,Leilei Gao

Iodoacetamide (IAcAm) is a harmful disinfection by-product. Studies have demonstrated that IAcAm can produce toxic effects in various tissues; however, its effect on female reproductive function remains unclear. To explore the effects of IAcAm on ovaries, we constructed a female mouse IAcAm toxicity model of free drinking model. The findings indicated that IAcAm exposure for five weeks did not affect the body growth of mice but increased the ovary/body weight ratio. At the tissue level, the numbers of atretic follicles increased. After the exposure, ovarian and blood samples were collected for analysis. IAcAm exposure caused changes in serum sex hormone levels, with an increase in follicle-stimulating hormone concentration(follicle-stimulating hormone) and a decrease in anti-Müllerian hormone concentration (anti-Müllerian hormone). Subsequent investigations revealed that IAcAm activated the transforming growth factor-β (TGF-β) signaling pathway and promoted ovarian fibrosis in mice. Simultaneously, IAcAm stimulated the granulosa cell apoptosis pathway and promoted granulosa cell apoptosis. Moreover, IAcAm interfered with mitochondrial function and increased reactive oxygen species, leading to a decrease in oocyte developmental potential. In conclusion, IAcAm exposure causes ovarian inflammation and leads to mitochondrial dysfunction in oocytes, affecting follicle maturation and reducing oocyte quality.

CAS / MDL: 144-48-9
研究领域: 生殖生物学 · 毒理学 · 分子生物学
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Oxidative Medicine and Cellular Longevity · 2020 · IF 5.076

Metformin Prevents Follicular Atresia in Aging Laying Chickens through Activation of PI3K/AKT and Calcium Signaling Pathways

Jinwei Yao,Yanfen Ma,Shuo Zhou,Tingting Bao,Yuling Mi,Weidong Zeng,Jian Li,Caiqiao Zhang

Increased follicular atresia occurs with aging and results in reduced fecundity in laying chickens. Therefore, relieving follicular atresia of aging poultry is a crucial measure to maintain sustained high laying performance. As an antiaging agent, metformin was reported to play important roles in preventing aging in diverse animals. In this study, the physiological state of the prehierarchical follicles in the peak-laying hens (D280) and aged hens (D580) was compared, followed with exploration for the possible capacity of metformin in delaying atresia of the prehierarchical follicles in the aged D580 hens. Results showed that the capacity of yolk deposition within follicles declined with aging, and the point of endoplasmic reticulum- (ER-) mitochondrion contact decreased in the ultrastructure of the follicular cells. Meanwhile, the expression of apoptosis signaling genes was increased in the atretic small white follicles. Subsequently, the H2O2-induced follicular atresia model was established to evaluate the enhancing capacity of metformin on yolk deposition and inhibition of apoptosis in the atretic small white follicles. Metformin inhibited apoptosis through regulating cooperation of the mitochondrion-associated ER membranes and the insulin (PI3K/AKT) signaling pathway. Furthermore, metformin regulated calcium ion homeostasis to relieve ER-stress and inhibited release of mitochondrion apoptosis factors (BAD and caspase). Additionally, metformin activated PI3K/AKT that suppressed activation of BAD (downstream of the insulin signaling pathway) in the atretic follicles. Further, serum estrogen level and liver estrogen receptor-α expression were increased after dietary metformin supplementation in D580 hens. These results indicated that administration of dietary metformin activated the PI3K/AKT and calcium signaling pathway and enhanced yolk deposition to prevent chicken follicular atresia.

研究领域: 动物科学 · 生殖生物学 · 分子生物学 · 营养学
✓ 已验证 DOI PubMed 高影响因子
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Veterinary Sciences · 2024 ·Vol. 11 ·期 12 ·619 · IF 2

Effects of Trace Elements and Vitamins on the Synthesis of Steroid Hormones in Follicular Granulosa Cells of Yak

Yanbing Lou,Tingting Yang,Yanqiu Zhu,Chenglong Xia,Hengmin Cui,Huidan Deng,Yixin Huang,Jing Fang,Zhicai Zuo,Hongrui Guo

Simple SummaryYak is a unique species of highland cattle that inhabits cold regions year-round. Poor soil conditions lead to low nutrient content in forage, making yaks susceptible to trace element deficiencies. This deficiency results in reduced reproductive rates and overall productivity in yaks. Hormones synthesized by the granulosa cells of yak follicles play a crucial role in yak reproduction. In this study, the changes in cell viability, hormone secretion, and hormone synthesis-related genes were observed by adding metal trace elements and vitamins to the culture medium of cultured granulosa cells of yak follicles in vitro. The results showed that the addition of certain trace elements and vitamins had a positive effect on the activity and hormone secretion of granulosa cells in yak follicles. These findings offer a potential solution for enhancing the reproductive performance of female yaks affected by trace element deficiencies.Yak (Bos grunniens), a special breed of cattle on the Qinghai–Tibet Plateau, has low fertility due to nutritional deficiency, especially the trace elements. The steroid hormones estradiol (E2) and progesterone (P4) synthesized by yak follicular granulosa cells (BGCs) are involved in the entire reproductive process. In the present study, we investigated the effects of trace elements and vitamins on yak follicular GCs, including the cellular activity, the synthesis of E2 and P4, and the expression of genes related to steroid hormone synthesis. The results showed that moderate supplementation of vitamin D3 (VD3), strontium (Sr), manganese (Mn), and selenium (Se) enhanced granulosa cell activity. Within the safe dose range, the addition of vitamin A (VA), VD3, cobalt (Co), Sr, copper (Cu), Mn, Se, and chromium (Cr) significantly increased the synthesis of E2 by GCs, while the addition of VA, vitamin C (VC), VE, zinc (Zn), Sr, Cu, and Cr enhanced the production of P4 in GCs. The changes in steroid synthesizing genes were consistent with the changes in hormone synthesis. This study provides an experimental basis for the addition of trace elements to improve the production performance of yaks.

研究领域: 动物科学 · 生殖生物学 · 营养学
✓ 已验证 DOI PubMed 高影响因子
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