Pub Date : 2025-01-28DOI: 10.1016/j.reprotox.2025.108848
Nara Kim , Jae Hoon Lee , Inha Lee , Joo Hyun Park , Gee Soo Jung , Min Jung Lee , Wooseok Im , SiHyun Cho , Young Sik Choi
Nanoplastics (NPs) and microplastics (MPs) have become a global concern in recent years. Most current research on the impact of plastics on obstetrics has focused on their accumulation in specific tissues in animal models and the disease-causing potential of MPs. However, there is a relative lack of research on the cellular changes caused by the accumulation of MPs.
In this study, we aimed to establish a proper in vitro exposure protocol for polystyrene (PS)-NPs and MPs and to investigate possible cytotoxic effects of PS-NPs and MPs on human endometrial stromal cells (ESCs) using different plastic sizes and concentrations. The results showed that smaller plastics, specifically 100 nm PS-NPs and 1 μm PS-MPs, had a higher cellular uptake propensity than larger particles, such as 5 μm PS-MPs, with significant morphological changes and cell death observed at concentrations above 100 μg/mL a 24-h period. In addition, confocal microscopy and real-time imaging confirmed the accumulation of these particles in the nucleus and cytoplasm, with internalization rates correlating with particle size. Also, 100 nm PS-NPs reduced cell proliferation and induced apoptosis. In conclusion, this study demonstrates that exposure to 100 nm PS-NPs and 1 μm PS-MPs leads to dynamic accumulation in ESCs, resulting in cell death or decreased proliferation at specific concentrations, which highlights the potential cellular toxicity of NPs or MPs.
{"title":"Investigation of potential toxic effects of nano- and microplastics on human endometrial stromal cells","authors":"Nara Kim , Jae Hoon Lee , Inha Lee , Joo Hyun Park , Gee Soo Jung , Min Jung Lee , Wooseok Im , SiHyun Cho , Young Sik Choi","doi":"10.1016/j.reprotox.2025.108848","DOIUrl":"10.1016/j.reprotox.2025.108848","url":null,"abstract":"<div><div>Nanoplastics (NPs) and microplastics (MPs) have become a global concern in recent years. Most current research on the impact of plastics on obstetrics has focused on their accumulation in specific tissues in animal models and the disease-causing potential of MPs. However, there is a relative lack of research on the cellular changes caused by the accumulation of MPs.</div><div>In this study, we aimed to establish a proper in vitro exposure protocol for polystyrene (PS)-NPs and MPs and to investigate possible cytotoxic effects of PS-NPs and MPs on human endometrial stromal cells (ESCs) using different plastic sizes and concentrations. The results showed that smaller plastics, specifically 100 nm PS-NPs and 1 μm PS-MPs, had a higher cellular uptake propensity than larger particles, such as 5 μm PS-MPs, with significant morphological changes and cell death observed at concentrations above 100 μg/mL a 24-h period. In addition, confocal microscopy and real-time imaging confirmed the accumulation of these particles in the nucleus and cytoplasm, with internalization rates correlating with particle size. Also, 100 nm PS-NPs reduced cell proliferation and induced apoptosis. In conclusion, this study demonstrates that exposure to 100 nm PS-NPs and 1 μm PS-MPs leads to dynamic accumulation in ESCs, resulting in cell death or decreased proliferation at specific concentrations, which highlights the potential cellular toxicity of NPs or MPs.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108848"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-26DOI: 10.1016/j.reprotox.2025.108844
Gaby Judith Quispe Palomino , Rensson Homero Céliz Ygnacio , Laritza Ferreira de Lima , Alesandro Silva Ferreira , João Elmo da Cunha Neto , Gildas Mbemya Tetaping , Francisco Denilson Rodrigues Gomes , Otilia Deusdênia Loiola Pessoa , Ramon da Silva Raposo , Danilo Damasceno Rocha , Cláudia do Ó Pessoa , José Ricardo Figueiredo , Naiza Arcângela Ribeiro de Sá , Ana Paula Ribeiro Rodrigues
This study aimed to investigate, in vitro, the toxicity of WTA on ovarian follicles. Initially, a cytotoxicity assay was conducted using tumor and non-tumor cell lines to determine the IC. Initially, a cytotoxicity assay was conducted using tumor and non-tumor cell lines to determine the IC50 of the WTA and validate its antitumor activity. Mouse ovaries were cultured in vitro (IVC) for 6 days in the presence of 1 % dimethyl sulfoxide (DMSO), doxorubicin at 0.3 µg/mL (DXR), or WTA at 0.6 µM or 6.0 µM. DXR or WTA were added to the IVC medium once (1DXR, 1WTA0.6, 1WTA6.0) or three times (3DXR, 3WTA0.6, 3WTA6.0). After the IVC, the ovarian stroma, follicular morphology and development, cell proliferation, senescence, DNA damage, and apoptosis were assessed. The degeneration rate in 3DXR and WTA6.0 (1x and 3x) was higher (p < 0.05) compared to the DMSO group. 1DXR and 3WTA0.6 reduced (p < 0.05) the percentage of primordial follicles and increased (p < 0.05) the number of developing follicles compared to the control (CTR) and DMSO groups. An increase (p < 0.05) in lipofuscin granules was observed with DXR and WTA at both concentrations and exposure frequencies compared to the CTR. In the presence of 3WTA0.6, staining for cleaved caspase-3 was more pronounced (p < 0.05). Additionally, 3WTA0.6, 1WTA6.0, and 3DXR increased (p < 0.05) DNA fragmentation in the stroma compared to the CTR and DMSO groups. We conclude that, like chemotherapy agents used for cancer treatment, WTA induces severe cytotoxic effects on ovarian follicles and stroma, especially at high concentrations and exposure frequencies.
{"title":"Investigations on the effects of in vitro exposure of mouse ovaries to withaferin A, a new candidate for chemotherapy","authors":"Gaby Judith Quispe Palomino , Rensson Homero Céliz Ygnacio , Laritza Ferreira de Lima , Alesandro Silva Ferreira , João Elmo da Cunha Neto , Gildas Mbemya Tetaping , Francisco Denilson Rodrigues Gomes , Otilia Deusdênia Loiola Pessoa , Ramon da Silva Raposo , Danilo Damasceno Rocha , Cláudia do Ó Pessoa , José Ricardo Figueiredo , Naiza Arcângela Ribeiro de Sá , Ana Paula Ribeiro Rodrigues","doi":"10.1016/j.reprotox.2025.108844","DOIUrl":"10.1016/j.reprotox.2025.108844","url":null,"abstract":"<div><div>This study aimed to investigate, <em>in vitro</em>, the toxicity of WTA on ovarian follicles. Initially, a cytotoxicity assay was conducted using tumor and non-tumor cell lines to determine the IC. Initially, a cytotoxicity assay was conducted using tumor and non-tumor cell lines to determine the IC<sub>50</sub> of the WTA and validate its antitumor activity. Mouse ovaries were cultured <em>in vitro</em> (IVC) for 6 days in the presence of 1 % dimethyl sulfoxide (DMSO), doxorubicin at 0.3 µg/mL (DXR), or WTA at 0.6 µM or 6.0 µM. DXR or WTA were added to the IVC medium once (<sub>1</sub>DXR, <sub>1</sub>WTA0.6, <sub>1</sub>WTA6.0) or three times (<sub>3</sub>DXR, <sub>3</sub>WTA0.6, <sub>3</sub>WTA6.0). After the IVC, the ovarian stroma, follicular morphology and development, cell proliferation, senescence, DNA damage, and apoptosis were assessed. The degeneration rate in <sub>3</sub>DXR and WTA6.0 (1x and 3x) was higher (p < 0.05) compared to the DMSO group. <sub>1</sub>DXR and <sub>3</sub>WTA0.6 reduced (p < 0.05) the percentage of primordial follicles and increased (p < 0.05) the number of developing follicles compared to the control (CTR) and DMSO groups. An increase (p < 0.05) in lipofuscin granules was observed with DXR and WTA at both concentrations and exposure frequencies compared to the CTR. In the presence of <sub>3</sub>WTA0.6, staining for cleaved caspase-3 was more pronounced (p < 0.05). Additionally, <sub>3</sub>WTA0.6, <sub>1</sub>WTA6.0, and <sub>3</sub>DXR increased (p < 0.05) DNA fragmentation in the stroma compared to the CTR and DMSO groups. We conclude that, like chemotherapy agents used for cancer treatment, WTA induces severe cytotoxic effects on ovarian follicles and stroma, especially at high concentrations and exposure frequencies.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108844"},"PeriodicalIF":3.3,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143060398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1016/j.reprotox.2024.108828
Hemily Batista-Silva , Nicolas Elie , Fátima Regina Mena Barreto Silva , Christelle Delalande
This study investigated the effects of bisphenol A (BPA) and the involvement of nuclear estrogen receptors (ESR) on testicular energy metabolism and spermatogenesis in zebrafish. Testes were incubated with DMSO, 10 pM or 10 μM BPA for 6 or 72 h, with some samples pre-incubated with the ESRα/β antagonist ICI 182,780. Gene and protein expressions were analyzed using real-time PCR and Western blot, respectively. Additionally, immunohistochemistry assessed protein expression, and testicular cell surface proportions were analyzed with Ilastik software. Results showed that 10 pM BPA (6 h) increased the expression of lactate dehydrogenase (ldhba), alanine aminotransferase (gpt2), pyruvate carboxylase, estrogen receptor β1 (esr2b), and P-element induced wimpy testis-like. After 72 h, outer dense fiber protein 3b expression decreased through ESRα/β, and BPA reduced spermatid and spermatozoa proportions, also mediated by ESRα/β activation. Moreover, 10 pM BPA decreased pyruvate kinase M1/2a (pkma) expression, whereas 10 μM BPA reduced gpt2 and estrogen-related receptor levels, as well as increased monocarboxylate transporter 4 (mct4), estrogen receptor β2 (esr2b) and synaptonemal complex protein 3 (scp3) expressions. Furthermore, the reduced relative expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and ldhba, as well as increased expression of glycogen phosphorylase by 10 μM BPA were dependent on ESRα/β. Additionally, BPA affected cell numbers expressing LDH and PKM via ESRα/β and increased the immunocontent of PKMA, PCNA, and ERK 1/2 phosphorylation. These results indicate that exposure of male fish to environmental concentrations of BPA impairs testicular energy metabolism and spermatogenesis in zebrafish through ESRα/β activation.
{"title":"In vitro bisphenol A impairs testicular energy metabolism and spermatogenesis through nuclear estrogen receptors activation in zebrafish","authors":"Hemily Batista-Silva , Nicolas Elie , Fátima Regina Mena Barreto Silva , Christelle Delalande","doi":"10.1016/j.reprotox.2024.108828","DOIUrl":"10.1016/j.reprotox.2024.108828","url":null,"abstract":"<div><div>This study investigated the effects of bisphenol A (BPA) and the involvement of nuclear estrogen receptors (ESR) on testicular energy metabolism and spermatogenesis in zebrafish. Testes were incubated with DMSO, 10 pM or 10 μM BPA for 6 or 72 h, with some samples pre-incubated with the ESRα/β antagonist ICI 182,780. Gene and protein expressions were analyzed using real-time PCR and Western blot, respectively. Additionally, immunohistochemistry assessed protein expression, and testicular cell surface proportions were analyzed with Ilastik software. Results showed that 10 pM BPA (6 h) increased the expression of lactate dehydrogenase (<em>ldhba</em>), alanine aminotransferase (<em>gpt2</em>), pyruvate carboxylase, estrogen receptor β1 (<em>esr2b</em>), and P-element induced wimpy testis-like. After 72 h, outer dense fiber protein 3b expression decreased through ESRα/β, and BPA reduced spermatid and spermatozoa proportions, also mediated by ESRα/β activation. Moreover, 10 pM BPA decreased pyruvate kinase M1/2a (<em>pkma</em>) expression, whereas 10 μM BPA reduced <em>gpt2</em> and estrogen-related receptor levels, as well as increased monocarboxylate transporter 4 (<em>mct4</em>), estrogen receptor β2 (e<em>sr2b</em>) and synaptonemal complex protein 3 (<em>scp3</em>) expressions. Furthermore, the reduced relative expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and <em>ldhba</em>, as well as increased expression of glycogen phosphorylase by 10 μM BPA were dependent on ESRα/β. Additionally, BPA affected cell numbers expressing LDH and PKM via ESRα/β and increased the immunocontent of PKMA, PCNA, and ERK 1/2 phosphorylation. These results indicate that exposure of male fish to environmental concentrations of BPA impairs testicular energy metabolism and spermatogenesis in zebrafish through ESRα/β activation.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108828"},"PeriodicalIF":3.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1016/j.reprotox.2025.108841
Emily Allard-Phillips , Shruti Kolli , Alice Rhoton-Vlasak , Kevin Campbell
This study explores the effects of calcium channel blockers (CCBs) on sperm function, a critical aspect of male fertility. Male infertility, responsible for 30–50 % of infertility cases, often involves issues with sperm motility and capacitation, both of which are heavily influenced by calcium ions and specific ion channels like CatSper and voltage-dependent calcium channels (VDCCs). CCBs, which are commonly prescribed for cardiovascular conditions, inhibit these calcium channels, potentially disrupting sperm function. A comprehensive literature review showed varied results: some studies demonstrated that CCBs such as nifedipine reduce sperm motility and the acrosome reaction, causing reversible infertility, while others found no significant impact on fertilization rates in IVF treatments. Supporting these findings, animal studies indicated that CCBs impair spermatogenesis and sperm function without necessarily affecting hormonal levels. The research suggests that the impact of CCBs on male fertility might be reversible, emphasizing the need for more extensive in vivo studies to further understand these effects and their clinical significance for patients on CCB therapy.
{"title":"Systematic review of the impact of calcium channel blockers on sperm function","authors":"Emily Allard-Phillips , Shruti Kolli , Alice Rhoton-Vlasak , Kevin Campbell","doi":"10.1016/j.reprotox.2025.108841","DOIUrl":"10.1016/j.reprotox.2025.108841","url":null,"abstract":"<div><div>This study explores the effects of calcium channel blockers (CCBs) on sperm function, a critical aspect of male fertility. Male infertility, responsible for 30–50 % of infertility cases, often involves issues with sperm motility and capacitation, both of which are heavily influenced by calcium ions and specific ion channels like CatSper and voltage-dependent calcium channels (VDCCs). CCBs, which are commonly prescribed for cardiovascular conditions, inhibit these calcium channels, potentially disrupting sperm function. A comprehensive literature review showed varied results: some studies demonstrated that CCBs such as nifedipine reduce sperm motility and the acrosome reaction, causing reversible infertility, while others found no significant impact on fertilization rates in IVF treatments. Supporting these findings, animal studies indicated that CCBs impair spermatogenesis and sperm function without necessarily affecting hormonal levels. The research suggests that the impact of CCBs on male fertility might be reversible, emphasizing the need for more extensive in vivo studies to further understand these effects and their clinical significance for patients on CCB therapy.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108841"},"PeriodicalIF":3.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1016/j.reprotox.2025.108837
Jonathan S. Ball , Anna Tochwin , Matthew J. Winter , Maciej Trznadel , Richard Currie , Kathryn Wolton , Julian M. French , Malcolm J. Hetheridge , Charles R. Tyler
With the US Environment Protection Agency reducing requests for (and funding of) mammalian studies alongside the proposed elimination of requests by 2035, there is an urgent need for fully validated New Approach Methods (NAMs) to fill the resultant gap for safety assessment of agrochemicals. One promising NAM for assessing the potential for human prenatal developmental toxicity potential is the Zebrafish Embryo Developmental Toxicity Assessment, a bioassay that has been used by the pharmaceutical industry for more than a decade in early-stage drug safety assessment. Despite its promise, little data has been generated to assess the validity of ZEDTA for assessing Developmental and Reproductive Toxicity of new agrochemical products. Addressing this knowledge gap, we tested 67 compounds (insecticides, herbicides and fungicides) spanning multiple different chemical groupings and mechanisms of action. ZEDTA assay results were compared with the European Chemicals Agency (ECHA) Classification and Labelling (C&L) for mammalian hazard classification and with publicly available data to determine the ZEDTA’s translation power. Overall, the ZEDTA assay had an effective detection capability of 65 % for sensitivity and 64 % for specificity as compared with the ECHA-C&L classification and publicly available data. Comparing the ZEDTA data there were both strengths and weaknesses in alignments for across the different chemical classes and chemical mechanisms of action. Overall, the data generated, show the performance of the ZEDTA assay was comparable with other bioassays highlighted as alternatives for mammalian assessment and holds good promise as a NAM for screening agrochemical prenatal developmental toxicity during new product human safety assessment.
{"title":"Determination of the zebrafish embryo developmental toxicity assessment (ZEDTA) as an alternative non-mammalian approach for the safety assessment of agrochemicals","authors":"Jonathan S. Ball , Anna Tochwin , Matthew J. Winter , Maciej Trznadel , Richard Currie , Kathryn Wolton , Julian M. French , Malcolm J. Hetheridge , Charles R. Tyler","doi":"10.1016/j.reprotox.2025.108837","DOIUrl":"10.1016/j.reprotox.2025.108837","url":null,"abstract":"<div><div>With the US Environment Protection Agency reducing requests for (and funding of) mammalian studies alongside the proposed elimination of requests by 2035, there is an urgent need for fully validated New Approach Methods (NAMs) to fill the resultant gap for safety assessment of agrochemicals. One promising NAM for assessing the potential for human prenatal developmental toxicity potential is the Zebrafish Embryo Developmental Toxicity Assessment, a bioassay that has been used by the pharmaceutical industry for more than a decade in early-stage drug safety assessment. Despite its promise, little data has been generated to assess the validity of ZEDTA for assessing Developmental and Reproductive Toxicity of new agrochemical products. Addressing this knowledge gap, we tested 67 compounds (insecticides, herbicides and fungicides) spanning multiple different chemical groupings and mechanisms of action. ZEDTA assay results were compared with the European Chemicals Agency (ECHA) Classification and Labelling (C&L) for mammalian hazard classification and with publicly available data to determine the ZEDTA’s translation power. Overall, the ZEDTA assay had an effective detection capability of 65 % for sensitivity and 64 % for specificity as compared with the ECHA-C&L classification and publicly available data. Comparing the ZEDTA data there were both strengths and weaknesses in alignments for across the different chemical classes and chemical mechanisms of action. Overall, the data generated, show the performance of the ZEDTA assay was comparable with other bioassays highlighted as alternatives for mammalian assessment and holds good promise as a NAM for screening agrochemical prenatal developmental toxicity during new product human safety assessment.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108837"},"PeriodicalIF":3.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-21DOI: 10.1016/j.reprotox.2025.108838
Josef P. Magyar, Roxana Simon, Monika Petus, Krisztina Rigó
One of the main endpoints for the evaluation of Developmental and Reproductive Toxicology (DART) studies is the determination of potential effects of a test substance on the skeleton during foetal development. In the course of a DART study according to the OECD 414 guideline, 400–500 gestational day 20-old (GD20), alizarin red and alcian blue-stained (ARAB) rat foetuses have to be assessed by a teratology expert, which is a time consuming and sub-optimally documented process. We have developed a method which allows for a standardised, comprehensive, quick and easy to perform, head-to-toe digital documentation of ARAB-stained GD20 rat foetuses. The method consists of the acquiring a video-stream or a time lapse-recording of foetuses, which for this purpose are axially rotated in a custom-made device. The obtained digital material is suitable for the complete visual inspection of stained foetal specimen from all sides in great detail, and thus can replace the conventional inspection under a binocular microscope, and might render the archiving of such specimen unnecessary.
{"title":"Comprehensive digital documentation of teratology studies","authors":"Josef P. Magyar, Roxana Simon, Monika Petus, Krisztina Rigó","doi":"10.1016/j.reprotox.2025.108838","DOIUrl":"10.1016/j.reprotox.2025.108838","url":null,"abstract":"<div><div>One of the main endpoints for the evaluation of Developmental and Reproductive Toxicology (DART) studies is the determination of potential effects of a test substance on the skeleton during foetal development. In the course of a DART study according to the OECD 414 guideline, 400–500 gestational day 20-old (GD20), alizarin red and alcian blue-stained (ARAB) rat foetuses have to be assessed by a teratology expert, which is a time consuming and sub-optimally documented process. We have developed a method which allows for a standardised, comprehensive, quick and easy to perform, head-to-toe digital documentation of ARAB-stained GD20 rat foetuses. The method consists of the acquiring a video-stream or a time lapse-recording of foetuses, which for this purpose are axially rotated in a custom-made device. The obtained digital material is suitable for the complete visual inspection of stained foetal specimen from all sides in great detail, and thus can replace the conventional inspection under a binocular microscope, and might render the archiving of such specimen unnecessary.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108838"},"PeriodicalIF":3.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.reprotox.2025.108840
Yingwei Chen , Ying Xiong , Lu Zhu , Longjie Gu , Yi Liu
Fluoxetine, a widely used selective serotonin reuptake inhibitor (SSRI), is highly effective in treating psychiatric disorders such as depression. Recently, its potential negative impact on male reproductive function has recently raised concerns, but it remains unknown whether testicular damage from long-term fluoxetine exposure can recover after stopping the drug. In this study, male C57BL/6 mice were divided into control (saline) and treatment (fluoxetine, 20 mg/kg.d) groups, administered orally for 4 weeks. This duration and dosage have been proven to demonstrate significant antidepressant effects in mice. Fertility assessments and euthanasia was then performed at three time points: immediately after treatment cessation, 4 weeks post-discontinuation, and 8 weeks post-discontinuation (n = 8). Results found that following long-term fluoxetine administration, male mice exhibited significantly reduced mating and fertility indices, decreased sperm count and motility, and increased sperm deformities compared to the control group. Testicular histology showed immature germ cells within the seminiferous tubule lumens, along with significantly reduced seminiferous epithelial thickness, seminiferous tubule diameter, and Johnsen score. Ki67 (proliferation marker) expression decreased, while Caspase3 (apoptosis marker) increased. By 4 weeks post-discontinuation, Ki67 and Caspase3 levels in the fluoxetine-treated group returned to control levels, with partial recovery in other parameters. By 8 weeks, all measured parameters had largely normalized, indicating significant recovery in reproductive function. These findings provided novel insights into fluoxetine's reproductive toxicity and were crucial for assessing its clinical safety in drug evaluations.
{"title":"Long-term oral fluoxetine leads to reduced male reproductive function in mice and gradual recovery after discontinuation","authors":"Yingwei Chen , Ying Xiong , Lu Zhu , Longjie Gu , Yi Liu","doi":"10.1016/j.reprotox.2025.108840","DOIUrl":"10.1016/j.reprotox.2025.108840","url":null,"abstract":"<div><div>Fluoxetine, a widely used selective serotonin reuptake inhibitor (SSRI), is highly effective in treating psychiatric disorders such as depression. Recently, its potential negative impact on male reproductive function has recently raised concerns, but it remains unknown whether testicular damage from long-term fluoxetine exposure can recover after stopping the drug. In this study, male C57BL/6 mice were divided into control (saline) and treatment (fluoxetine, 20 mg/kg.d) groups, administered orally for 4 weeks. This duration and dosage have been proven to demonstrate significant antidepressant effects in mice. Fertility assessments and euthanasia was then performed at three time points: immediately after treatment cessation, 4 weeks post-discontinuation, and 8 weeks post-discontinuation (n = 8). Results found that following long-term fluoxetine administration, male mice exhibited significantly reduced mating and fertility indices, decreased sperm count and motility, and increased sperm deformities compared to the control group. Testicular histology showed immature germ cells within the seminiferous tubule lumens, along with significantly reduced seminiferous epithelial thickness, seminiferous tubule diameter, and Johnsen score. Ki67 (proliferation marker) expression decreased, while Caspase3 (apoptosis marker) increased. By 4 weeks post-discontinuation, Ki67 and Caspase3 levels in the fluoxetine-treated group returned to control levels, with partial recovery in other parameters. By 8 weeks, all measured parameters had largely normalized, indicating significant recovery in reproductive function. These findings provided novel insights into fluoxetine's reproductive toxicity and were crucial for assessing its clinical safety in drug evaluations.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108840"},"PeriodicalIF":3.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicotine is one of the most toxic substances found in cigarettes, but also found in chewing tobacco gum, patches and vaping products (electronic cigarettes). In addition to being a highly addictive chemical, it is capable of reducing fertility in men and women. In the ovaries, it can induce morphological changes and impair the formation of follicles, being a possible cause of changes in the reproductive cycle and anticipation of menopause in women whose mothers smoked during pregnancy. By increasing the generation of free radicals, nicotine can induce oxidation in biological samples and change the expression of inflammatory cytokines. It damages the immune system and many other cells of newborns exposed prenatally. Despite its teratogenic potential, many women continue to use this drug during pregnancy and lactation. Thus, this work aims to analyze the effects of maternal exposure to nicotine on the ovaries of adult rats. To this end, 10 rats received nicotine throughout pregnancy and lactation. Their offspring were euthanized around 90 days-old, in the metestrus phase, for ovary collection and analysis of oxidative stress and inflammation. The results showed that exposure to nicotine increased MDA level, but did not cause damage to the DNA of ovarian cells (8-OHdG). It also increased IL-1β and anti-inflammatory protein AnxA1 and receptor Fpr1, and reduced the mast cell population in ovaries. We concluded that maternal exposure to nicotine is capable of inducing oxidative stress and leading to inflammatory changes in the ovaries of adult offspring exposed during the intrauterine and breastfeeding phases.
{"title":"Maternal exposure to nicotine causes oxidative stress and inflammatory changes in the ovaries of rats’ adult offspring","authors":"I.M.M. Freitas , I.D. Santos , J.C. Souza , G.S. Souza , L.W. Fischer , R.A. Da Silva , C.D. Gil , C.C. Paccola","doi":"10.1016/j.reprotox.2025.108839","DOIUrl":"10.1016/j.reprotox.2025.108839","url":null,"abstract":"<div><div>Nicotine is one of the most toxic substances found in cigarettes, but also found in chewing tobacco gum, patches and vaping products (electronic cigarettes). In addition to being a highly addictive chemical, it is capable of reducing fertility in men and women. In the ovaries, it can induce morphological changes and impair the formation of follicles, being a possible cause of changes in the reproductive cycle and anticipation of menopause in women whose mothers smoked during pregnancy. By increasing the generation of free radicals, nicotine can induce oxidation in biological samples and change the expression of inflammatory cytokines. It damages the immune system and many other cells of newborns exposed prenatally. Despite its teratogenic potential, many women continue to use this drug during pregnancy and lactation. Thus, this work aims to analyze the effects of maternal exposure to nicotine on the ovaries of adult rats. To this end, 10 rats received nicotine throughout pregnancy and lactation. Their offspring were euthanized around 90 days-old, in the metestrus phase, for ovary collection and analysis of oxidative stress and inflammation. The results showed that exposure to nicotine increased MDA level, but did not cause damage to the DNA of ovarian cells (8-OHdG). It also increased IL-1β and anti-inflammatory protein AnxA1 and receptor Fpr1, and reduced the mast cell population in ovaries. We concluded that maternal exposure to nicotine is capable of inducing oxidative stress and leading to inflammatory changes in the ovaries of adult offspring exposed during the intrauterine and breastfeeding phases.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108839"},"PeriodicalIF":3.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-10DOI: 10.1016/j.reprotox.2025.108836
Ayodeji Ojo Oteyola , Isadora Maria Sátiro de Oliveira , Jonathas Medeiros de Almeida , Lucas Carvalho Cardoso , Thais de Merici Domingues e Paula , Julia Meireles Nogueira , Jade Carceroni de Sousa Carvalho , Henrique Martins Nogueira , Brenda Lee Simas Porto , Ana Paula Lucas Mota , Paulo Henrique Almeida Campos-Junior , Erika Cristina Jorge , Fernanda Radicchi Campos Lobato de Almeida
Saturated fat has been linked to cardiovascular diseases, leading to an increase in polyunsaturated fat consumption. The aim of the present study was to investigate the effects of three fat sources (coconut oil, lard and soybean oil) on metabolic and reproductive parameters in heterogenic mice. Female Swiss mice (5–6 weeks old; n = 9/group) were divided into four experimental groups: control (CC), coconut oil (CO), lard (LA), and soybean oil (SO), and were orally given 0.6 mL of the corresponding fat daily for 6 weeks to further investigate morphological, biochemical, and molecular parameters. SO females showed the highest glucose intolerance (P < 0.05), and all experimental groups were highly insulin resistant, with no statistical differences among them (P > 0.05). Moreover, all fat supplemented groups presented increased proportion in bile ducts, and CO and SO females presented higher LDL-cholesterol levels compared to CC (P < 0.05). Regarding reproductive parameters, estrous cycle alterations were observed mainly in the SO group, showing extended luteal phase duration (longer diestrus), and higher numbers of atretic follicles per area compared to the CC females (P < 0.05). Furthermore, higher proportion of active Casp-3 positive cells in the granulosa layers of preantral follicles were observed in the LA compared to the CO group (P < 0.05). The gene expression data revealed downregulation of Igf1r and Acvr1 in SO, upregulation of Igf1r in LA and Lhcgr in CO compared to CC females (P < 0.05). Thus, excessive fat intake may have deleterious effects on metabolism and reproductive function, but lard may be the least harmful source.
{"title":"Chronic fat consumption affects metabolic aspects of murine physiology and influences ovarian follicle atresia","authors":"Ayodeji Ojo Oteyola , Isadora Maria Sátiro de Oliveira , Jonathas Medeiros de Almeida , Lucas Carvalho Cardoso , Thais de Merici Domingues e Paula , Julia Meireles Nogueira , Jade Carceroni de Sousa Carvalho , Henrique Martins Nogueira , Brenda Lee Simas Porto , Ana Paula Lucas Mota , Paulo Henrique Almeida Campos-Junior , Erika Cristina Jorge , Fernanda Radicchi Campos Lobato de Almeida","doi":"10.1016/j.reprotox.2025.108836","DOIUrl":"10.1016/j.reprotox.2025.108836","url":null,"abstract":"<div><div>Saturated fat has been linked to cardiovascular diseases, leading to an increase in polyunsaturated fat consumption. The aim of the present study was to investigate the effects of three fat sources (coconut oil, lard and soybean oil) on metabolic and reproductive parameters in heterogenic mice. Female Swiss mice (5–6 weeks old; n = 9/group) were divided into four experimental groups: control (CC), coconut oil (CO), lard (LA), and soybean oil (SO), and were orally given 0.6 mL of the corresponding fat daily for 6 weeks to further investigate morphological, biochemical, and molecular parameters. SO females showed the highest glucose intolerance (P < 0.05), and all experimental groups were highly insulin resistant, with no statistical differences among them (P > 0.05). Moreover, all fat supplemented groups presented increased proportion in bile ducts, and CO and SO females presented higher LDL-cholesterol levels compared to CC (P < 0.05). Regarding reproductive parameters, estrous cycle alterations were observed mainly in the SO group, showing extended luteal phase duration (longer diestrus), and higher numbers of atretic follicles per area compared to the CC females (P < 0.05). Furthermore, higher proportion of active Casp-3 positive cells in the granulosa layers of preantral follicles were observed in the LA compared to the CO group (P < 0.05). The gene expression data revealed downregulation of <em>Igf1r</em> and <em>Acvr1</em> in SO, upregulation of <em>Igf1r</em> in LA and <em>Lhcgr</em> in CO compared to CC females (P < 0.05). Thus, excessive fat intake may have deleterious effects on metabolism and reproductive function, but lard may be the least harmful source.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108836"},"PeriodicalIF":3.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-10DOI: 10.1016/j.reprotox.2025.108835
Kristina Vacy , Thusi Rupasinghe , Alicia Bjorksten , Andrea Gogos , Peter J. Meikle , Satvika Burugupalli , Wah Chin Boon , Anne-Louise Ponsonby , Barwon Infant Study Investigator Group
Phthalates are ubiquitous environmental pollutants known for their endocrine-disrupting properties, particularly during critical periods such as pregnancy and early childhood. Phthalates alter lipid metabolism, but the role of prenatal exposure on the offspring lipidome is less understood. In particular, we focused on long chain acylcarnitines - intermediates of fatty acid oxidation that serve as potential biomarkers of mitochondrial function and energy metabolism. This study aimed (i) to investigate the association between prenatal phthalate exposure and the child’s blood acylcarnitine concentrations and, (ii) to evaluate the impact of prenatal administration of di-(2-ethylhexyl) phthalate (DEHP) on acylcarnitine levels in mouse offspring blood, brain and liver. We conducted analyses of both a prospective birth cohort study and an experimental study in mice. From the Barwon Infant Study cohort (1074 mother-child pairs), prenatal phthalate exposure was assessed at 36 weeks' gestation and its association with acylcarnitine levels was examined in cord blood, and child’s blood at 6 months, 12 months and 4 years. In mice, pregnant C57BL/6 J mouse dams were exposed to 20 μg/kg DEHP for 5 days mid-gestation, and offspring tissues were analyzed at 1 month of age postnatally for acylcarnitine profiles. Our findings demonstrate that prenatal phthalate levels (specifically butyl benzyl phthalate (BBzP) and diisobutyl phthalate (DiBP)) are inversely associated with total long chain acylcarnitine levels in human cord blood at birth. In contrast, BBzP was positively associated with the long chain acylcarnitines at 12 months of age. In mice, prenatal DEHP exposure for only 5 days led to decreased palmitoylcarnitine (AC16:0) levels in the brain and liver, but not in blood. Taken together, our findings highlight that prenatal phthalate exposure can alter acylcarnitine profiles, indicating disruptions in fatty acid metabolism that may have long-term effects on metabolic health.
{"title":"The associations between prenatal plastic phthalate exposure and lipid acylcarnitine levels in humans and mice","authors":"Kristina Vacy , Thusi Rupasinghe , Alicia Bjorksten , Andrea Gogos , Peter J. Meikle , Satvika Burugupalli , Wah Chin Boon , Anne-Louise Ponsonby , Barwon Infant Study Investigator Group","doi":"10.1016/j.reprotox.2025.108835","DOIUrl":"10.1016/j.reprotox.2025.108835","url":null,"abstract":"<div><div>Phthalates are ubiquitous environmental pollutants known for their endocrine-disrupting properties, particularly during critical periods such as pregnancy and early childhood. Phthalates alter lipid metabolism, but the role of prenatal exposure on the offspring lipidome is less understood. In particular, we focused on long chain acylcarnitines - intermediates of fatty acid oxidation that serve as potential biomarkers of mitochondrial function and energy metabolism. This study aimed (i) to investigate the association between prenatal phthalate exposure and the child’s blood acylcarnitine concentrations and, (ii) to evaluate the impact of prenatal administration of di-(2-ethylhexyl) phthalate (DEHP) on acylcarnitine levels in mouse offspring blood, brain and liver. We conducted analyses of both a prospective birth cohort study and an experimental study in mice. From the Barwon Infant Study cohort (1074 mother-child pairs), prenatal phthalate exposure was assessed at 36 weeks' gestation and its association with acylcarnitine levels was examined in cord blood, and child’s blood at 6 months, 12 months and 4 years. In mice, pregnant C57BL/6 J mouse dams were exposed to 20 μg/kg DEHP for 5 days mid-gestation, and offspring tissues were analyzed at 1 month of age postnatally for acylcarnitine profiles. Our findings demonstrate that prenatal phthalate levels (specifically butyl benzyl phthalate (BBzP) and diisobutyl phthalate (DiBP)) are inversely associated with total long chain acylcarnitine levels in human cord blood at birth. In contrast, BBzP was positively associated with the long chain acylcarnitines at 12 months of age. In mice, prenatal DEHP exposure for only 5 days led to decreased palmitoylcarnitine (AC16:0) levels in the brain and liver, but not in blood. Taken together, our findings highlight that prenatal phthalate exposure can alter acylcarnitine profiles, indicating disruptions in fatty acid metabolism that may have long-term effects on metabolic health.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108835"},"PeriodicalIF":3.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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