Pub Date : 2024-10-16DOI: 10.1016/j.reprotox.2024.108735
Jasmeena Jan , Showkeen Muzamil Bashir , Wajid Mohammad Sheikh , Owais Mohmad Bhat , Towseef Amin Rafeeqi , Showkat Ahmad Shah , Abid Hamid Dar , Mohammad Afzal Zargar , Nissar Ahmad Wani
The study assessed histological, biochemical, oxidative stress, and molecular parameters to evaluate the consequences of Chlorpyrifos and Dimethoate exposure on uterine health in female rats. Despite showing no obvious signs of toxicity apart from minor clinical symptoms in DM-exposed rats, both pesticides caused degenerative changes in uterine tissue. This study demonstrates that pesticides induce inflammatory responses and oxidative stress in rats, by NF-κB activation and altering antioxidant enzyme levels. Besides, CPF and DM exposure disrupted gene expression of HOXA10, HOXA11, and WNT and reduced activation of β-catenin in the uterus, which is crucial for implantation and reproductive function. These findings suggest that pesticide exposure may impair reproductive health and fertility in females, highlighting potential implications for human health.
{"title":"Chlorpyrifos and dimethoate exposure impairs female fertility by deregulating WNT signaling pathway & uterine receptivity","authors":"Jasmeena Jan , Showkeen Muzamil Bashir , Wajid Mohammad Sheikh , Owais Mohmad Bhat , Towseef Amin Rafeeqi , Showkat Ahmad Shah , Abid Hamid Dar , Mohammad Afzal Zargar , Nissar Ahmad Wani","doi":"10.1016/j.reprotox.2024.108735","DOIUrl":"10.1016/j.reprotox.2024.108735","url":null,"abstract":"<div><div>The study assessed histological, biochemical, oxidative stress, and molecular parameters to evaluate the consequences of Chlorpyrifos and Dimethoate exposure on uterine health in female rats. Despite showing no obvious signs of toxicity apart from minor clinical symptoms in DM-exposed rats, both pesticides caused degenerative changes in uterine tissue. This study demonstrates that pesticides induce inflammatory responses and oxidative stress in rats, by NF-κB activation and altering antioxidant enzyme levels. Besides, CPF and DM exposure disrupted gene expression of HOXA10, HOXA11, and WNT and reduced activation of β-catenin in the uterus, which is crucial for implantation and reproductive function. These findings suggest that pesticide exposure may impair reproductive health and fertility in females, highlighting potential implications for human health.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108735"},"PeriodicalIF":3.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473605","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 : 2024-10-13DOI: 10.1016/j.reprotox.2024.108734
ChengLu Wang , JiaCheng Zhang , Fang Gao , Min Zheng , XiaoHua Fu , KeBing Yang
Notable variations in semen parameters among non-smoking males have been documented post-COVID-19 pandemic. The role of smoking as a significant contributing factor to male infertility has been substantiated. Does the combined effect of smoking and SARS-CoV-2 infection impact male reproductive function? A prospective descriptive cohort study was performed using data from 90 smoking and 90 non-smoking males before and after coronavirus infection in a single center over a period of 3 months. Semen samples were collected before and within 15 days after COVID-19 infection, ensuring no more than three months elapsed between the two collections. The semen parameters evaluated included volume, concentration, progressive motility, normal morphology, and DNA fragmentation rate. Proteomic and metabolomic studies were further used to explore the differences between groups. Both non-smokers and smokers exhibited a marked reduction in sperm concentration, progressive motility, and normal morphology rate. Additionally, an increase in sperm DNA fragmentation index was noted for non-smokers and smokers. In the non-smoking group, dysregulation proteins including SEMG1, SEMG2 and DNAH5, and metabolites including L-glutamine, cis-9-Palmitoleic acid and Linoleamide were observed. In smokers, dysregulation proteins including SMCP, ROPN1B and IZUMO4, alongside metabolites including carnitine, gamma-Glutamylglutamic acid, and hypoxanthine were found. Comparative analysis between smoking and non-smoking patients post-COVID-19 also revealed significant differences in semen concentration, morphology and sperm DNA fragmentation rate. Dysregulated proteins including HSPA5, HSPA2 and PGK2, and metabolites such as acetylcarnitine, oxaloacetate and nicotinate were associated with impaired sperm function. Our study demonstrates that the virus also significantly compromises sperm quality in smoking males, who experience more pronounced declines post-infection compared to their non-smoking counterparts. This research underscores the necessity for comprehensive fertility assessments for smoking males after recovering from COVID-19.
{"title":"Investigating the effects of COVID-19 on sperm in male smokers: A prospective integrated proteomic and metabolomic study","authors":"ChengLu Wang , JiaCheng Zhang , Fang Gao , Min Zheng , XiaoHua Fu , KeBing Yang","doi":"10.1016/j.reprotox.2024.108734","DOIUrl":"10.1016/j.reprotox.2024.108734","url":null,"abstract":"<div><div>Notable variations in semen parameters among non-smoking males have been documented post-COVID-19 pandemic. The role of smoking as a significant contributing factor to male infertility has been substantiated. Does the combined effect of smoking and SARS-CoV-2 infection impact male reproductive function? A prospective descriptive cohort study was performed using data from 90 smoking and 90 non-smoking males before and after coronavirus infection in a single center over a period of 3 months. Semen samples were collected before and within 15 days after COVID-19 infection, ensuring no more than three months elapsed between the two collections. The semen parameters evaluated included volume, concentration, progressive motility, normal morphology, and DNA fragmentation rate. Proteomic and metabolomic studies were further used to explore the differences between groups. Both non-smokers and smokers exhibited a marked reduction in sperm concentration, progressive motility, and normal morphology rate. Additionally, an increase in sperm DNA fragmentation index was noted for non-smokers and smokers. In the non-smoking group, dysregulation proteins including SEMG1, SEMG2 and DNAH5, and metabolites including L-glutamine, cis-9-Palmitoleic acid and Linoleamide were observed. In smokers, dysregulation proteins including SMCP, ROPN1B and IZUMO4, alongside metabolites including carnitine, gamma-Glutamylglutamic acid, and hypoxanthine were found. Comparative analysis between smoking and non-smoking patients post-COVID-19 also revealed significant differences in semen concentration, morphology and sperm DNA fragmentation rate. Dysregulated proteins including HSPA5, HSPA2 and PGK2, and metabolites such as acetylcarnitine, oxaloacetate and nicotinate were associated with impaired sperm function. Our study demonstrates that the virus also significantly compromises sperm quality in smoking males, who experience more pronounced declines post-infection compared to their non-smoking counterparts. This research underscores the necessity for comprehensive fertility assessments for smoking males after recovering from COVID-19.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108734"},"PeriodicalIF":3.3,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442054","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 : 2024-10-12DOI: 10.1016/j.reprotox.2024.108731
Yaxin Zhang , Dongliang Xu , Shuaixing Song , Guoxu Wang , Hexin Su , Yang Wu , Yuwei Zhang , Hongyan Liu , Qingfu Li , Xiangdong Wang , Zengli Yu , Xiaozhuan Liu
In utero exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can contribute to high rates of cleft palate (CP) formation, but the mechanistic basis for these effects remains uncertain. Here, multi-omics-based metabolomic and transcriptomic analyses were employed to characterize the etiological basis for TCDD-induced CP on gestational day 14.5 (GD14.5). These analyses revealed that TCDD-induced CP formation is associated with calcium, MAPK, PI3K-Akt, and mTOR pathway signaling. PI3K-Akt and mTOR signaling activity is closely linked with the maintenance of cellular proliferation and survival. Moreover, mTOR-mediated regulation of autophagic activity is essential for ensuring an appropriate balance between metabolic activity and growth. Murine embryonic palatal mesenchymal (MEPM) cell proliferation was thus characterized, autophagic activity in these cells was evaluated through electron microscopy and western immunoblotting was used to compare the levels of autophagy- and AKT/mTOR-related protein between the control and TCDD groups on GD14.5. These analyses indicated that MEPM cell proliferative and autophagic activity was inhibited in response to TCDD exposure with the concomitant activation of AKT/mTOR signaling, in line with the multi-omics data. Together, these findings suggested that following TCDD exposure, the activation of AKT/mTOR-related autophagic signaling may play a role in the loss of appropriate palatal cell homeostasis, culminating in the incidence of CP.
{"title":"AKT/mTOR-mediated autophagic signaling is associated with TCDD-induced cleft palate","authors":"Yaxin Zhang , Dongliang Xu , Shuaixing Song , Guoxu Wang , Hexin Su , Yang Wu , Yuwei Zhang , Hongyan Liu , Qingfu Li , Xiangdong Wang , Zengli Yu , Xiaozhuan Liu","doi":"10.1016/j.reprotox.2024.108731","DOIUrl":"10.1016/j.reprotox.2024.108731","url":null,"abstract":"<div><div>In utero exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can contribute to high rates of cleft palate (CP) formation, but the mechanistic basis for these effects remains uncertain. Here, multi-omics-based metabolomic and transcriptomic analyses were employed to characterize the etiological basis for TCDD-induced CP on gestational day 14.5 (GD14.5). These analyses revealed that TCDD-induced CP formation is associated with calcium, MAPK, PI3K-Akt, and mTOR pathway signaling. PI3K-Akt and mTOR signaling activity is closely linked with the maintenance of cellular proliferation and survival. Moreover, mTOR-mediated regulation of autophagic activity is essential for ensuring an appropriate balance between metabolic activity and growth. Murine embryonic palatal mesenchymal (MEPM) cell proliferation was thus characterized, autophagic activity in these cells was evaluated through electron microscopy and western immunoblotting was used to compare the levels of autophagy- and AKT/mTOR-related protein between the control and TCDD groups on GD14.5. These analyses indicated that MEPM cell proliferative and autophagic activity was inhibited in response to TCDD exposure with the concomitant activation of AKT/mTOR signaling, in line with the multi-omics data. Together, these findings suggested that following TCDD exposure, the activation of AKT/mTOR-related autophagic signaling may play a role in the loss of appropriate palatal cell homeostasis, culminating in the incidence of CP.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108731"},"PeriodicalIF":3.3,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473604","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 : 2024-10-11DOI: 10.1016/j.reprotox.2024.108733
Darja Lavogina , Keiu Kask , Sergei Kopanchuk , Nadja Visser , Mary Laws , Jodi A. Flaws , Theodora Kunovac Kallak , Matts Olovsson , Pauliina Damdimopoulou , Andres Salumets
Phthalate monoesters have been identified as endocrine disruptors in a variety of models, yet understanding of their exact mechanisms of action and molecular targets in cells remains incomplete. Here, we set to determine whether epidemiologically relevant mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) can affect biological processes by altering cell plasma membrane fluidity or formation of cell-cell contacts. As a model system, we chose endometrial stromal cell lines, one of which was previously used in a transcriptomic study with MEHHP or MEHHP-containing mixtures. A short-term exposure (1 h) of membrane preparations to endocrine disruptors was sufficient to induce changes in membrane fluidity/rigidity, whereas different mixtures showed different effects at various depths of the bilayer. A longer exposure (96 h) affected the ability of cells to form spheroids and highlighted issues with membrane integrity in loosely assembled spheroids. Finally, in spheroids assembled from T-HESC cells, MEHHP interfered with the formation of cell-cell contacts as indicated by the immunostaining of zonula occludens 1 protein. Overall, this study emphasized the need to consider plasma membrane, membrane-bound organelles, and secretory vesicles as possible biological targets of endocrine disruptors and offered an explanation for a multitude of endocrine disruptor roles documented earlier.
{"title":"Phthalate monoesters affect membrane fluidity and cell-cell contacts in endometrial stromal adherent cell lines and spheroids","authors":"Darja Lavogina , Keiu Kask , Sergei Kopanchuk , Nadja Visser , Mary Laws , Jodi A. Flaws , Theodora Kunovac Kallak , Matts Olovsson , Pauliina Damdimopoulou , Andres Salumets","doi":"10.1016/j.reprotox.2024.108733","DOIUrl":"10.1016/j.reprotox.2024.108733","url":null,"abstract":"<div><div>Phthalate monoesters have been identified as endocrine disruptors in a variety of models, yet understanding of their exact mechanisms of action and molecular targets in cells remains incomplete. Here, we set to determine whether epidemiologically relevant mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) can affect biological processes by altering cell plasma membrane fluidity or formation of cell-cell contacts. As a model system, we chose endometrial stromal cell lines, one of which was previously used in a transcriptomic study with MEHHP or MEHHP-containing mixtures. A short-term exposure (1 h) of membrane preparations to endocrine disruptors was sufficient to induce changes in membrane fluidity/rigidity, whereas different mixtures showed different effects at various depths of the bilayer. A longer exposure (96 h) affected the ability of cells to form spheroids and highlighted issues with membrane integrity in loosely assembled spheroids. Finally, in spheroids assembled from T-HESC cells, MEHHP interfered with the formation of cell-cell contacts as indicated by the immunostaining of <em>zonula occludens</em> 1 protein. Overall, this study emphasized the need to consider plasma membrane, membrane-bound organelles, and secretory vesicles as possible biological targets of endocrine disruptors and offered an explanation for a multitude of endocrine disruptor roles documented earlier.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108733"},"PeriodicalIF":3.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433217","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 : 2024-10-11DOI: 10.1016/j.reprotox.2024.108725
Julia R Varshavsky, Juleen Lam, Courtney Cooper, Patrick Allard, Jennifer Fung, Ashwini Oke, Ravinder Kumar, Joshua F Robinson, Tracey J Woodruff
While high-throughput (HTP) assays have been proposed as platforms to rapidly assess reproductive toxicity, there is currently a lack of established assays that specifically address germline development/function and fertility. We assessed the applicability domains of yeast (S. cerevisiae) and nematode (C. elegans) HTP assays in toxicity screening of 124 environmental chemicals, determining their agreement in identifying toxicants and their concordance with reproductive toxicity in vivo. We integrated data generated in the two models and compared results using a streamlined, semi-automated benchmark dose (BMD) modeling approach. We then extracted and modeled relevant mammalian in vivo data available for the matching chemicals included in the Toxicological Reference Database (ToxRefDB). We ranked potencies of common compounds using the BMD and evaluated correlation between the datasets using Pearson and Spearman correlation coefficients. We found moderate to good correlation across the three data sets, with r = 0.48 (95 % CI: 0.28-1.00, p<0.001) and rs = 0.40 (p=0.002) for the parametric and rank order correlations between the HTP BMDs; r = 0.95 (95 % CI: 0.76-1.00, p=0.0005) and rs = 0.89 (p=0.006) between the yeast assay and ToxRefDB BMDs; and r = 0.81 (95 % CI: 0.28-1.00, p=0.014) and rs = 0.75 (p=0.033) between the worm assay and ToxRefDB BMDs. Our findings underscore the potential of these HTP assays to identify environmental chemicals that exhibit reproductive toxicity. Integrating these HTP datasets into mammalian in vivo prediction models using machine learning methods could further enhance their predictive value in future rapid screening efforts.
{"title":"Analyzing high-throughput assay data to advance the rapid screening of environmental chemicals for human reproductive toxicity.","authors":"Julia R Varshavsky, Juleen Lam, Courtney Cooper, Patrick Allard, Jennifer Fung, Ashwini Oke, Ravinder Kumar, Joshua F Robinson, Tracey J Woodruff","doi":"10.1016/j.reprotox.2024.108725","DOIUrl":"https://doi.org/10.1016/j.reprotox.2024.108725","url":null,"abstract":"<p><p>While high-throughput (HTP) assays have been proposed as platforms to rapidly assess reproductive toxicity, there is currently a lack of established assays that specifically address germline development/function and fertility. We assessed the applicability domains of yeast (S. cerevisiae) and nematode (C. elegans) HTP assays in toxicity screening of 124 environmental chemicals, determining their agreement in identifying toxicants and their concordance with reproductive toxicity in vivo. We integrated data generated in the two models and compared results using a streamlined, semi-automated benchmark dose (BMD) modeling approach. We then extracted and modeled relevant mammalian in vivo data available for the matching chemicals included in the Toxicological Reference Database (ToxRefDB). We ranked potencies of common compounds using the BMD and evaluated correlation between the datasets using Pearson and Spearman correlation coefficients. We found moderate to good correlation across the three data sets, with r = 0.48 (95 % CI: 0.28-1.00, p<0.001) and r<sub>s</sub> = 0.40 (p=0.002) for the parametric and rank order correlations between the HTP BMDs; r = 0.95 (95 % CI: 0.76-1.00, p=0.0005) and r<sub>s</sub> = 0.89 (p=0.006) between the yeast assay and ToxRefDB BMDs; and r = 0.81 (95 % CI: 0.28-1.00, p=0.014) and r<sub>s</sub> = 0.75 (p=0.033) between the worm assay and ToxRefDB BMDs. Our findings underscore the potential of these HTP assays to identify environmental chemicals that exhibit reproductive toxicity. Integrating these HTP datasets into mammalian in vivo prediction models using machine learning methods could further enhance their predictive value in future rapid screening efforts.</p>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":" ","pages":"108725"},"PeriodicalIF":3.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473602","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 : 2024-10-10DOI: 10.1016/j.reprotox.2024.108732
Itishree Dubey , Nandheeswari K , Vigneshwaran G , Gourav Rohilla , Lalruatmawii , Pratik Naxine , Jayapradha P , Mahesh Rachamalla , Sapana Kushwaha
The gut system, commonly referred to as one of the principal organs of the human "superorganism," is a home to trillions of bacteria and serves an essential physiological function in male reproductive failures or infertility. The interaction of the endocrine-immune system and the microbiome facilitates reproduction as a multi-network system. Some recent studies that link gut microbiota to male infertility are questionable. Is the gut-testis axis (GTA) real, and does it affect male infertility? As a result, this review emphasizes the interconnected links between gut health and male reproductive function via changes in gut microbiota. However, a variety of harmful (endocrine disruptors, heavy metals, pollutants, and antibiotics) and favorable (a healthy diet, supplements, and phytoconstituents) elements promote microbiota by causing dysbiosis and symbiosis, respectively, which eventually modify the activities of male reproductive organs and their hormones. The findings of preclinical and clinical studies on the direct and indirect effects of microbiota changes on testicular functions have revealed a viable strategy for exploring the GTA-axis. Although the GTA axis is poorly understood, it may have potential ties to reproductive issues that can be used for therapeutic purposes in the future.
{"title":"Exploring the hypothetical links between environmental pollutants, diet, and the gut-testis axis: The potential role of microbes in male reproductive health","authors":"Itishree Dubey , Nandheeswari K , Vigneshwaran G , Gourav Rohilla , Lalruatmawii , Pratik Naxine , Jayapradha P , Mahesh Rachamalla , Sapana Kushwaha","doi":"10.1016/j.reprotox.2024.108732","DOIUrl":"10.1016/j.reprotox.2024.108732","url":null,"abstract":"<div><div>The gut system, commonly referred to as one of the principal organs of the human \"superorganism,\" is a home to trillions of bacteria and serves an essential physiological function in male reproductive failures or infertility. The interaction of the endocrine-immune system and the microbiome facilitates reproduction as a multi-network system. Some recent studies that link gut microbiota to male infertility are questionable. Is the gut-testis axis (GTA) real, and does it affect male infertility? As a result, this review emphasizes the interconnected links between gut health and male reproductive function <em>via</em> changes in gut microbiota. However, a variety of harmful (endocrine disruptors, heavy metals, pollutants, and antibiotics) and favorable (a healthy diet, supplements, and phytoconstituents) elements promote microbiota by causing dysbiosis and symbiosis, respectively, which eventually modify the activities of male reproductive organs and their hormones. The findings of preclinical and clinical studies on the direct and indirect effects of microbiota changes on testicular functions have revealed a viable strategy for exploring the GTA-axis. Although the GTA axis is poorly understood, it may have potential ties to reproductive issues that can be used for therapeutic purposes in the future.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108732"},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433218","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 : 2024-10-05DOI: 10.1016/j.reprotox.2024.108730
Houpeng Wang , Cheng Cheng , Jing Ding , Ruirui Qian , Tao Luo , Liping Zheng , Ying Chen
A strong link between antipsychotic drug use and reduced human sperm quality has been reported. Trifluoperazine (TFP), a commonly used antipsychotic, is now being explored for anticancer applications. Although there are hints that TFP might affect the male reproductive system, its impact on human sperm quality remains uncertain. Using a human sperm and TFP in vitro coculture system, we examined the effect of TFP (12.5, 25, 50 and 100 μM) on human sperm function and physiological parameters. The results showed that 50 μM and 100 μM TFP induced the accumulation of reactive oxygen species (ROS) and a decrease in the mitochondrial membrane potential (MMP) of human sperm, leading to decreased sperm viability, while 25 μM TFP inhibited only the penetration ability, total sperm motility, and progressive motility. Although 12.5 μM and 25 μM TFP increased [Ca2+]i in human sperm, they did not affect capacitation or the acrosome reaction. These results may be explained by the observation that 12.5 μM and 25 μM TFP did not increase tyrosine phosphorylation in human sperm, although TFP increased [Ca2+]i in a time-course traces similar to that of progesterone. Our results indicated that TFP could cause male reproductive toxicity by inducing the accumulation of ROS and a decrease in the MMP in human sperm.
{"title":"Trifluoperazine effect on human sperm: The accumulation of reactive oxygen species and the decrease in the mitochondrial membrane potential","authors":"Houpeng Wang , Cheng Cheng , Jing Ding , Ruirui Qian , Tao Luo , Liping Zheng , Ying Chen","doi":"10.1016/j.reprotox.2024.108730","DOIUrl":"10.1016/j.reprotox.2024.108730","url":null,"abstract":"<div><div>A strong link between antipsychotic drug use and reduced human sperm quality has been reported. Trifluoperazine (TFP), a commonly used antipsychotic, is now being explored for anticancer applications. Although there are hints that TFP might affect the male reproductive system, its impact on human sperm quality remains uncertain. Using a human sperm and TFP in vitro coculture system, we examined the effect of TFP (12.5, 25, 50 and 100 μM) on human sperm function and physiological parameters. The results showed that 50 μM and 100 μM TFP induced the accumulation of reactive oxygen species (ROS) and a decrease in the mitochondrial membrane potential (MMP) of human sperm, leading to decreased sperm viability, while 25 μM TFP inhibited only the penetration ability, total sperm motility, and progressive motility. Although 12.5 μM and 25 μM TFP increased [Ca<sup>2+</sup>]<sub>i</sub> in human sperm, they did not affect capacitation or the acrosome reaction. These results may be explained by the observation that 12.5 μM and 25 μM TFP did not increase tyrosine phosphorylation in human sperm, although TFP increased [Ca<sup>2+</sup>]<sub>i</sub> in a time-course traces similar to that of progesterone. Our results indicated that TFP could cause male reproductive toxicity by inducing the accumulation of ROS and a decrease in the MMP in human sperm.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108730"},"PeriodicalIF":3.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381582","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 : 2024-10-02DOI: 10.1016/j.reprotox.2024.108729
Eric W. Fish , Karen E. Boschen , Scott E. Parnell
Alcohol exposure during the gastrulation stage of development can disrupt Sonic hedgehog (Shh) signaling and cause eye, craniofacial, and brain defects. One of the genes that regulates Shh signaling is Efcab7, which encodes a protein that facilitates the actions of Smoothened (Smo), a critical component of the Shh pathway. Previous work from our lab has demonstrated that Efcab7 is differentially expressed between two sub-strains of C57BL/6 mice that differ in their sensitivity to gastrulation-stage alcohol exposure. The more alcohol-sensitive C57BL/6 J mice express lower levels of Efcab7 during gastrulation than do the less alcohol-sensitive C57BL/6NHsd mice. The current study examined whether partial or full Efcab7 deletions render mice more sensitive to gastrulation-stage alcohol exposure and affect the sensitivity to other modulators of Shh signaling that cause craniofacial malformations. Efcab7+/- dams were mated with Efcab7+/- sires to produce Efcab7+/+, Efcab7+/-, and Efcab7-/- fetuses. On gestational day 7 (GD 7), they received either alcohol (two doses of 2.9 g/kg, i.p., given 4 hours apart), the Smo antagonist vismodegib (40 mg/kg, or vehicle, p.o.), the Smo agonist SAG (20 mg/kg) or the appropriate vehicles. GD 17 fetuses were collected and examined for ocular and craniofacial dysmorphology. As compared to Efcab7+/+ fetuses, Efcab7-/- fetuses exposed to alcohol or vismodegib treatment had more severe ocular and craniofacial malformations. In contrast, Efcab7-/- fetuses had less severe malformations induced by SAG. These results confirm that Efcab7 can modify responses to Shh agonists and antagonists and further identify Efcab7 as a gene important for the sensitivity to gastrulation-stage alcohol exposure.
{"title":"Efcab7 deletion sensitizes mice to the teratogenic effects of gastrulation-stage alcohol exposure","authors":"Eric W. Fish , Karen E. Boschen , Scott E. Parnell","doi":"10.1016/j.reprotox.2024.108729","DOIUrl":"10.1016/j.reprotox.2024.108729","url":null,"abstract":"<div><div>Alcohol exposure during the gastrulation stage of development can disrupt Sonic hedgehog (Shh) signaling and cause eye, craniofacial, and brain defects. One of the genes that regulates Shh signaling is <em>Efcab7,</em> which encodes a protein that facilitates the actions of Smoothened (Smo), a critical component of the Shh pathway. Previous work from our lab has demonstrated that <em>Efcab7</em> is differentially expressed between two sub-strains of C57BL/6 mice that differ in their sensitivity to gastrulation-stage alcohol exposure. The more alcohol-sensitive C57BL/6 J mice express lower levels of <em>Efcab7</em> during gastrulation than do the less alcohol-sensitive C57BL/6NHsd mice. The current study examined whether partial or full <em>Efcab7</em> deletions render mice more sensitive to gastrulation-stage alcohol exposure and affect the sensitivity to other modulators of Shh signaling that cause craniofacial malformations. <em>Efcab7</em><sup><em>+/-</em></sup> dams were mated with <em>Efcab7</em><sup><em>+/-</em></sup> sires to produce <em>Efcab7</em><sup><em>+/+</em></sup>, <em>Efcab7</em><sup><em>+/-</em></sup>, and <em>Efcab7</em><sup><em>-/-</em></sup> fetuses. On gestational day 7 (GD 7), they received either alcohol (two doses of 2.9 g/kg, i.p., given 4 hours apart), the Smo antagonist vismodegib (40 mg/kg, or vehicle, p.o.), the Smo agonist SAG (20 mg/kg) or the appropriate vehicles. GD 17 fetuses were collected and examined for ocular and craniofacial dysmorphology. As compared to <em>Efcab7</em><sup><em>+/+</em></sup> fetuses, <em>Efcab7</em><sup><em>-/-</em></sup> fetuses exposed to alcohol or vismodegib treatment had more severe ocular and craniofacial malformations. In contrast, <em>Efcab7</em><sup><em>-/-</em></sup> fetuses had less severe malformations induced by SAG. These results confirm that <em>Efcab7</em> can modify responses to Shh agonists and antagonists and further identify <em>Efcab7</em> as a gene important for the sensitivity to gastrulation-stage alcohol exposure.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108729"},"PeriodicalIF":3.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375891","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 : 2024-09-28DOI: 10.1016/j.reprotox.2024.108722
Zachary W. Clark , Joshua P. Mogus , Jenna Marando, Reed S. Effenson, Laura N. Vandenberg
The mammary gland is responsive to endogenous hormones and environmental chemicals that are estrogen receptor (ER) agonists. The mouse mammary gland offers the opportunity to dissect the most sensitive windows of exposure. 17α-ethinyl estradiol (EE2) is a pharmaceutical ER agonist that often serves as a positive control for estrogen-active chemicals. Here, adult female mice were exposed to EE2 starting either at pregnancy day 7, or on lactational day 1, and exposures continued until the litters were weaned. The pups were therefore exposed during gestation + the juvenile period, or during the juvenile period alone. The morphology of the mammary gland was evaluated in both male and female offspring at two life stages: weaning (postnatal day [PND]21) and at puberty (PND32). Other hormone-sensitive outcomes evaluated included body weight, anogenital index, frequency of open vagina, and weight of the uterus. We found age- and sex-dependent effects of EE2 on these estrogen-responsive endpoints including the morphology of the mammary gland. Importantly, EE2 altered mammary gland morphology even when exposures were limited to the juvenile period. However, the number of endpoints that were affected in animals from the EE2-Juvenile-Only period were fewer, and typically of a lower magnitude, compared to those observed in the EE2-Gest-Juvenile group. Understanding the effects of environmental estrogen exposures during the juvenile period is critical because humans are exposed to estrogenic pollutants throughout life, including in early childhood.
{"title":"Vulnerable periods for the mouse mammary gland: Comparison of the effects of ethinyl estradiol exposures during two early stages of development","authors":"Zachary W. Clark , Joshua P. Mogus , Jenna Marando, Reed S. Effenson, Laura N. Vandenberg","doi":"10.1016/j.reprotox.2024.108722","DOIUrl":"10.1016/j.reprotox.2024.108722","url":null,"abstract":"<div><div>The mammary gland is responsive to endogenous hormones and environmental chemicals that are estrogen receptor (ER) agonists. The mouse mammary gland offers the opportunity to dissect the most sensitive windows of exposure. 17α-ethinyl estradiol (EE2) is a pharmaceutical ER agonist that often serves as a positive control for estrogen-active chemicals. Here, adult female mice were exposed to EE2 starting either at pregnancy day 7, or on lactational day 1, and exposures continued until the litters were weaned. The pups were therefore exposed during gestation + the juvenile period, or during the juvenile period alone. The morphology of the mammary gland was evaluated in both male and female offspring at two life stages: weaning (postnatal day [PND]21) and at puberty (PND32). Other hormone-sensitive outcomes evaluated included body weight, anogenital index, frequency of open vagina, and weight of the uterus. We found age- and sex-dependent effects of EE2 on these estrogen-responsive endpoints including the morphology of the mammary gland. Importantly, EE2 altered mammary gland morphology even when exposures were limited to the juvenile period. However, the number of endpoints that were affected in animals from the EE2-Juvenile-Only period were fewer, and typically of a lower magnitude, compared to those observed in the EE2-Gest-Juvenile group. Understanding the effects of environmental estrogen exposures during the juvenile period is critical because humans are exposed to estrogenic pollutants throughout life, including in early childhood.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108722"},"PeriodicalIF":3.3,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352917","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 : 2024-09-25DOI: 10.1016/j.reprotox.2024.108727
Paul Barrow
92 novel drugs were approved by the FDA in 2022–2023. 48 of these approvals were for orphan indications. Embryofetal development (EFD) studies were conducted for 79 % of approvals. Rats and rabbits were the most common species used (77 % and 62 % of studies, respectively). For the testing of biopharmaceuticals, rodents were more often used (43 % of EFD studies) than non-human primates (29 %) and rabbits (29 %). Most (75 %) biopharmaceuticals intended to treat cancer were approved without EFD studies. Amongst the 41 drugs for which both rat and rabbit EFD studies were performed, the rabbit appeared more sensitive to both maternal toxicity and developmental toxicity (61 % and 63 % of drugs, respectively). Most drugs (76 %) showed more than a 2-fold difference in the LOAEL for developmental toxicity between the rat and rabbit. EFD studies were not required for drugs with a mode of action known to pose a clear hazard for pregnancy and further EFD studies were generally not performed when clinically relevant developmental effects had already been observed in one species or in a preliminary EFD study. Many drug labels showed minor deviations from the PLLR rule: the metric used to calculate exposure margins and the presence or absence of maternal toxicity were not always specified. These omissions, however, are of little significance for the prescriber. The five reviews in this series now show compiled information on EFD studies for all small molecule pharmaceuticals approved since 2014 and for all therapeutic monoclonal antibodies approved to date.
{"title":"Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2022 and 2023","authors":"Paul Barrow","doi":"10.1016/j.reprotox.2024.108727","DOIUrl":"10.1016/j.reprotox.2024.108727","url":null,"abstract":"<div><div>92 novel drugs were approved by the FDA in 2022–2023. 48 of these approvals were for orphan indications. Embryofetal development (EFD) studies were conducted for 79 % of approvals. Rats and rabbits were the most common species used (77 % and 62 % of studies, respectively). For the testing of biopharmaceuticals, rodents were more often used (43 % of EFD studies) than non-human primates (29 %) and rabbits (29 %). Most (75 %) biopharmaceuticals intended to treat cancer were approved without EFD studies. Amongst the 41 drugs for which both rat and rabbit EFD studies were performed, the rabbit appeared more sensitive to both maternal toxicity and developmental toxicity (61 % and 63 % of drugs, respectively). Most drugs (76 %) showed more than a 2-fold difference in the LOAEL for developmental toxicity between the rat and rabbit. EFD studies were not required for drugs with a mode of action known to pose a clear hazard for pregnancy and further EFD studies were generally not performed when clinically relevant developmental effects had already been observed in one species or in a preliminary EFD study. Many drug labels showed minor deviations from the PLLR rule: the metric used to calculate exposure margins and the presence or absence of maternal toxicity were not always specified. These omissions, however, are of little significance for the prescriber. The five reviews in this series now show compiled information on EFD studies for all small molecule pharmaceuticals approved since 2014 and for all therapeutic monoclonal antibodies approved to date.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108727"},"PeriodicalIF":3.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352916","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}
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