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Biology and Toxicology of Gametes, Embryos, and Cancer Cells in Reproductive System

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 12071

Special Issue Editor

Prof. Dr. Youngsok Choi

E-Mail Website
Guest Editor
Department of Stem Cell and Regenerative Biotechnology and Humanized Pig Center (SRC), Konkuk Institute of Technology, Konkuk University, Seoul 05029, Republic of Korea
Interests: apoptosis regulatory proteins; von Hippel Lindau protein; apoptosis; fertility preservation; ovulation induction; vitrification; synaptonemal complex; meiosis; chromosome pairing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Reproductive development is very important for maintaining and preserving successful pregnancy in both males and females. In recent years, infertility has been increasing due to various factors that cause the abnormal development and differentiation of reproductive organs, including the testis, ovaries, and uterus. These include both genetic defects and environmental factors that result in malfunction of the reproductive system. Identifying the exact factors leading to the abnormal development and toxicity of reproductive organs throughout life is essential. This requires continued efforts, which will provide us with better knowledge in order to overcome infertility related to the development and toxicity of the reproductive system. In this Special Issue, we invite potential researchers who are working toward revealing the causes of infertility and solving this problem by investigating the development, differentiation, and toxicity of reproductive organs.

Prof. Dr. Youngsok Choi 
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • reproductive development
  • infertility
  • gonadotoxicity
  • environmental factors
  • cancer drugs

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Published Papers (7 papers)

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Editorial

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2 pages, 158 KiB  
Editorial
Biology and Toxicology of Gametes, Embryos, and Cancer Cells in Reproductive Systems
by Minju Kang, Byeongseok Kim and Youngsok Choi
Int. J. Mol. Sci. 2024, 25(7), 3639; https://doi.org/10.3390/ijms25073639 - 25 Mar 2024
Viewed by 386
Abstract
Reproduction is the important process of transmitting one’s genetic information to the next generation [...] Full article
(This article belongs to the Special Issue Biology and Toxicology of Gametes, Embryos, and Cancer Cells in Reproductive System)

Research

Jump to: Editorial

11 pages, 2320 KiB  
Article
Do Aging and Parity Affect VEGF-A/VEGFR Content and Signaling in the Ovary?—A Mouse Model Study
by Valentina Di Nisio, Gianna Rossi, Alessandro Chiominto, Ezio Pompili and Sandra Cecconi
Int. J. Mol. Sci. 2023, 24(4), 3318; https://doi.org/10.3390/ijms24043318 - 7 Feb 2023
Cited by 2 | Viewed by 1283
Abstract
In this study, the effects of aging and parity on VEGF-A/VEGFR protein content and signaling in the mice ovaries were determined. The research group consisted of nulliparous (virgins, V) and multiparous (M) mice during late-reproductive (L, 9–12 months) and post-reproductive (P, 15–18 months) [...] Read more.
In this study, the effects of aging and parity on VEGF-A/VEGFR protein content and signaling in the mice ovaries were determined. The research group consisted of nulliparous (virgins, V) and multiparous (M) mice during late-reproductive (L, 9–12 months) and post-reproductive (P, 15–18 months) stages. Whilst ovarian VEGFR1 and VEGFR2 remained unchanged in all the experimental groups (LM, LV, PM, PV), protein content of VEGF-A and phosphorylated VEGFR2 significantly decreased only in PM ovaries. VEGF-A/VEGFR2-dependent activation of ERK1/2, p38, as well as protein content of cyclin D1, cyclin E1, and Cdc25A were then assessed. In ovaries of LV and LM, all of these downstream effectors were maintained at a comparable low/undetectable level. Conversely, the decrease recorded in PM ovaries did not occur in the PV group, in which the significant increase of kinases and cyclins, as well phosphorylation levels mirrored the trend of the pro-angiogenic markers. Altogether, the present results demonstrated that, in mice, ovarian VEGF-A/VEGFR2 protein content and downstream signaling can be modulated in an age- and parity-dependent manner. Moreover, the lowest levels of pro-angiogenic and cell cycle progression markers detected in PM mouse ovaries sustains the hypothesis that parity could exert a protective role by downregulating the protein content of key mediators of pathological angiogenesis. Full article
(This article belongs to the Special Issue Biology and Toxicology of Gametes, Embryos, and Cancer Cells in Reproductive System)
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18 pages, 7457 KiB  
Article
The Activation of Reticulophagy by ER Stress through the ATF4-MAP1LC3A-CCPG1 Pathway in Ovarian Granulosa Cells Is Linked to Apoptosis and Necroptosis
by Huiduo Li, Yanan Jing, Xiaoya Qu, Jinyi Yang, Pengge Pan, Xinrui Liu, Hui Gao, Xiuying Pei, Cheng Zhang and Yanzhou Yang
Int. J. Mol. Sci. 2023, 24(3), 2749; https://doi.org/10.3390/ijms24032749 - 1 Feb 2023
Cited by 5 | Viewed by 2146
Abstract
Female infertility is caused by premature ovarian failure (POF), which is triggered by the endoplasmic reticulum (ER) stress-mediated apoptosis of granulosa cells. The ER unfolded protein response (UPRer) is initiated to promote cell survival by alleviating excessive ER stress, but cellular [...] Read more.
Female infertility is caused by premature ovarian failure (POF), which is triggered by the endoplasmic reticulum (ER) stress-mediated apoptosis of granulosa cells. The ER unfolded protein response (UPRer) is initiated to promote cell survival by alleviating excessive ER stress, but cellular apoptosis is induced by persistent or strong ER stress. Recent studies have reported that reticulophagy is initiated by ER stress. Whether reticulophagy is activated in the ER stress-mediated apoptosis of granulosa cells and which pathway is initiated to activate reticulophagy during the apoptosis of granulosa cells are unknown. Therefore, the role of reticulophagy in granulosa cell death and the relationship between ER stress and reticulophagy were investigated in this work. Our results suggest that the ER stress inducer tunicamycin causes POF in mice, which is attributed to the apoptosis of granulosa cells and is accompanied by the activation of UPRer and reticulophagy. Furthermore, granulosa cells were treated with tunicamycin, and granulosa cell apoptosis was triggered and increased the expression of UPRer and reticulophagy molecules. The expression of ATF4 was then downregulated by RNAi, which decreased the levels of autophagy and the reticulophagy receptor CCGP1. Furthermore, ATF4 targets MAP1LC3A, as revealed by the ChIP sequencing results, and co-IP results demonstrated that MAP1LC3A interacts with CCPG1. Therefore, reticulophagy was activated by ER stress through the ATF4-MAP1LC3A-CCPG1 pathway to mitigate ER stress. Additionally, the role of reticulophagy in granulosa cells was investigated by the knockdown of CCPG1 with RNAi. Interestingly, only a small number of granulosa cells died by apoptosis, whereas the death of most granulosa cells occurred by necroptosis triggered by STAT1 and STAT3 to impair ER proteostasis and the ER protein quality control system UPRer. Taken together, the results indicate that the necroptosis of granulosa cells is triggered by up- and downregulating the reticulophagy receptor CCPG1 through STAT1/STAT3-(p)RIPK1-(p)RIPK3-(p)MLKL and that reticulophagy is activated by ER stress through the ATF4-MAP1LC3A-CCPG1 pathway. Full article
(This article belongs to the Special Issue Biology and Toxicology of Gametes, Embryos, and Cancer Cells in Reproductive System)
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12 pages, 7850 KiB  
Article
MIG-6 Is Critical for Progesterone Responsiveness in Human Complex Atypical Hyperplasia and Early-Stage Endometrial Cancer
by Olivia Jeong, Russell R. Broaddus, Bruce A. Lessey, John I. Risinger, Mark I. Hunter and Tae Hoon Kim
Int. J. Mol. Sci. 2022, 23(23), 14596; https://doi.org/10.3390/ijms232314596 - 23 Nov 2022
Cited by 3 | Viewed by 1484
Abstract
Women with complex atypical hyperplasia (CAH) or early-stage endometrioid endometrial cancer (EEC) are candidates for fertility preservation. The most common approach is progesterone (P4) therapy and deferral of hysterectomy until after completion of childbearing. However, P4 therapy response rates vary, and molecular mechanisms [...] Read more.
Women with complex atypical hyperplasia (CAH) or early-stage endometrioid endometrial cancer (EEC) are candidates for fertility preservation. The most common approach is progesterone (P4) therapy and deferral of hysterectomy until after completion of childbearing. However, P4 therapy response rates vary, and molecular mechanisms behind P4 resistance are poorly understood. One potential molecular cause of P4 resistance is a loss or attenuation of PGR expression. Mitogen-inducible gene 6 (MIG-6) is critical for P4 responsiveness. MIG-6 protein expression in the endometrial epithelial and stromal cells from women with CAH and EEC was significantly lower compared to women without CAH or EEC. The P4-responsive women (10/15) exhibited an increase of MIG-6 expression in epithelial and stromal cells compared to P4-resistant women (5/15). In addition, immunohistochemical analysis for PGR results showed that stromal PGR levels are significantly higher in P4-responsive women compared to P4-resistant women, whereas epithelial PGR expression was not different. A reverse correlation of MIG-6 and pAKT levels was observed in early-stage EEC patients. Studies strongly suggest that loss of MIG-6 and PGR and activation of pAKT lead to P4 resistance in CAH and EEC. These results will help to elucidate the molecular mechanism leading to P4 resistance in CAH and EEC. Full article
(This article belongs to the Special Issue Biology and Toxicology of Gametes, Embryos, and Cancer Cells in Reproductive System)
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15 pages, 9885 KiB  
Article
Cisplatin Induces Apoptosis in Mouse Neonatal Testes Organ Culture
by Hyun-Jung Park, Ji-Soo Kim, Ran Lee and Hyuk Song
Int. J. Mol. Sci. 2022, 23(21), 13360; https://doi.org/10.3390/ijms232113360 - 1 Nov 2022
Cited by 5 | Viewed by 1726
Abstract
Chemotherapy is used for childhood cancer but may lead to infertility in patients. Spermatogonia stem cells are present in the testes of prepubertal boys, although they do not produce sperm at this age. Herein, we evaluated the toxicity of cisplatin, a known medicine [...] Read more.
Chemotherapy is used for childhood cancer but may lead to infertility in patients. Spermatogonia stem cells are present in the testes of prepubertal boys, although they do not produce sperm at this age. Herein, we evaluated the toxicity of cisplatin, a known medicine for cancer treatment, in neonatal mouse testes using in vitro organ culture. Mouse testicular fragments (MTFs) derived from 5.5-d postpartum mouse testes were exposed to 1–10 μg/mL cisplatin. The results showed that cisplatin significantly downregulated the expression of germ cell marker genes, including differentiated and undifferentiated, in a dose-dependent manner. In particular, a high dose of cisplatin (10 μg/mL) led to germ cell depletion. In addition, the expression levels of the Sertoli cell marker gene, the number of SOX9+ Sertoli cells, and the levels of SOX9 protein were markedly decreased in cisplatin-treated MTFs compared to controls. The mRNA expression of steroidogenic enzyme-related genes significantly increased in cisplatin-treated MTFs, except for estrogen receptor 1 (Esr1). Consistently, 3β-hydroxysteroid dehydrogenase protein was also observed in the interstitial regions of cisplatin-treated MTFs. Altogether, our findings showed a significant impairment in germ cell development, Sertoli cell survival, and steroidogenesis in the MTFs of cisplatin-treated mice. Full article
(This article belongs to the Special Issue Biology and Toxicology of Gametes, Embryos, and Cancer Cells in Reproductive System)
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14 pages, 2091 KiB  
Article
p53 Controls Meiotic Prophase Progression and Crossover Formation
by Marina Marcet-Ortega, Andros Maldonado-Linares, Maria López-Panadés and Ignasi Roig
Int. J. Mol. Sci. 2022, 23(17), 9818; https://doi.org/10.3390/ijms23179818 - 29 Aug 2022
Cited by 4 | Viewed by 1863
Abstract
Meiosis initiates with the formation of double strand breaks (DSBs) throughout the genome. To avoid genomic instability, these DSBs need to be correctly repaired by homologous recombination. Surveillance mechanisms involving the DNA damage response (DDR) pathway ATM-CHK2-p53 can detect the persistence of unrepaired [...] Read more.
Meiosis initiates with the formation of double strand breaks (DSBs) throughout the genome. To avoid genomic instability, these DSBs need to be correctly repaired by homologous recombination. Surveillance mechanisms involving the DNA damage response (DDR) pathway ATM-CHK2-p53 can detect the persistence of unrepaired DBSs and activate the recombination-dependent arrest at the pachytene stage. However, a complete understanding of p53 functions under normal physiological conditions remains lacking. Here, we report a detailed analysis of the p53 role during meiotic prophase in mice spermatocytes. We show that the absence of p53 regulates prophase progression by slowing down the pachytene stage when the recombination-dependent arrest occurs. Furthermore, our results show that p53 is necessary for proper crossover (CO) formation and localization. Our study contributes to a deeper understanding of p53 roles during the meiotic prophase. Full article
(This article belongs to the Special Issue Biology and Toxicology of Gametes, Embryos, and Cancer Cells in Reproductive System)
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12 pages, 4850 KiB  
Article
Estrogen Regulates the Expression and Localization of YAP in the Uterus of Mice
by Sohyeon Moon, Ok-Hee Lee, Byeongseok Kim, Jinju Park, Semi Hwang, Siyoung Lee, Giwan Lee, Hyukjung Kim, Hyuk Song, Kwonho Hong, Jaejin Cho and Youngsok Choi
Int. J. Mol. Sci. 2022, 23(17), 9772; https://doi.org/10.3390/ijms23179772 - 29 Aug 2022
Cited by 3 | Viewed by 2545
Abstract
The dynamics of uterine endometrium is important for successful establishment and maintenance of embryonic implantation and development, along with extensive cell differentiation and proliferation. The tissue event is precisely and complicatedly regulated as several signaling pathways are involved including two main hormones, estrogen [...] Read more.
The dynamics of uterine endometrium is important for successful establishment and maintenance of embryonic implantation and development, along with extensive cell differentiation and proliferation. The tissue event is precisely and complicatedly regulated as several signaling pathways are involved including two main hormones, estrogen and progesterone signaling. We previously showed a novel signaling molecule, Serine/threonine protein kinase 3/4 (STK3/4), which is responded to hormone in the mouse uterine epithelium. However, the role and regulation of its target, YES-associated protein (YAP) remains unknown. In this study, we investigated the expression and regulation of YAP in mouse endometrium. We found that YAP was periodically expressed in the endometrium during the estrous cycle. Furthermore, periodic expression of YAP was shown to be related to the pathway under hormone treatment. Interestingly, estrogen was shown to positively modulate YAP via endometrial epithelial receptors. In addition, the knockdown of YAP showed that YAP regulated various target genes in endometrial cells. The knockdown of YAP down-regulated numerous targets including ADAMTS1, AMOT, AMOTL1, ANKRD1, CTNNA1, MCL1. On the other hand, the expressions of AREG and AXL were increased by its knockdown. These findings imply that YAP responds via Hippo signaling under various intrauterine signals and is considered to play a role in the expression of factors important for uterine endometrium dynamic regulation. Full article
(This article belongs to the Special Issue Biology and Toxicology of Gametes, Embryos, and Cancer Cells in Reproductive System)
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