Pub Date : 2024-11-29DOI: 10.1016/j.reprotox.2024.108764
Jung-Chien Cheng , Qian Zhang , Lingling Zhang , Beibei Bi , Hailong Wang , Lanlan Fang , Hsun-Ming Chang , Ying-Pu Sun
Overdose of acetaminophen (APAP) has been shown to adversely affect the outcome of pregnancy. The steroidogenic acute regulatory protein (StAR) plays a pivotal role in steroidogenesis, but the impact of APAP on StAR expression in adult human ovarian granulosa cells remains elusive. Here, we demonstrate that APAP overdose leads to the downregulation of StAR expression in the human granulosa cell tumor cell line, KGN, and in the primary culture of human granulosa-lutein (hGL) cells. Treatment of overdose APAP inhibits the activation of the AKT signaling pathway and downregulates the expression of transcription factor SP1. Using a small molecule of AKT activator and SP1 overexpression approaches, we show that the suppressive effect of APAP on StAR expression is mediated through the inhibition of AKT-mediated upregulation of SP1 expression. This study contributes to a deeper understanding of the pharmacological actions of APAP and its impacts on female reproductive health.
{"title":"Acetaminophen overdose inhibits steroidogenic acute regulatory protein expression by reducing AKT-mediated SP1 expression in human granulosa-lutein cells","authors":"Jung-Chien Cheng , Qian Zhang , Lingling Zhang , Beibei Bi , Hailong Wang , Lanlan Fang , Hsun-Ming Chang , Ying-Pu Sun","doi":"10.1016/j.reprotox.2024.108764","DOIUrl":"10.1016/j.reprotox.2024.108764","url":null,"abstract":"<div><div>Overdose of acetaminophen (APAP) has been shown to adversely affect the outcome of pregnancy. The steroidogenic acute regulatory protein (StAR) plays a pivotal role in steroidogenesis, but the impact of APAP on StAR expression in adult human ovarian granulosa cells remains elusive. Here, we demonstrate that APAP overdose leads to the downregulation of StAR expression in the human granulosa cell tumor cell line, KGN, and in the primary culture of human granulosa-lutein (hGL) cells. Treatment of overdose APAP inhibits the activation of the AKT signaling pathway and downregulates the expression of transcription factor SP1. Using a small molecule of AKT activator and SP1 overexpression approaches, we show that the suppressive effect of APAP on StAR expression is mediated through the inhibition of AKT-mediated upregulation of SP1 expression. This study contributes to a deeper understanding of the pharmacological actions of APAP and its impacts on female reproductive health.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108764"},"PeriodicalIF":3.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772000","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 : 2024-11-28DOI: 10.1016/j.reprotox.2024.108760
Xueqin Feng , Hongwei Fu , Xiao Sun , Hua Shu , Yongning Zhu , Yanyan Bai , Qinggui Ren , Xinying Liu , Meng Liu , Fanyong Zhang , Yanping Wang
A high sucrose diet during pregnancy may generate profound effects on vascular diseases in offspring later in life. Pulmonary artery (PA) functions is closely related to pulmonary hypertension, but whether and how prenatal high-sucrose diet (HS) affect pulmonary vasoreactivity in adult offspring remains unknown. We investigated the alterations of PA reactivity in postnatal offspring exposed to prenatal HS. Pregnant Sprague-Dawley rats were fed either a tap water or 20 % high sucrose solution throughout pregnancy. Pulmonary arteries from adult offspring were isolated and tested for all experiments. Prenatal HS increased vascular wall thickness, resulted in swollen mitochondria, and altered myofilament distribution in vascular smooth muscle layers of PA. Notably, the offspring's PAs from HS group showed increased vasoconstriction, but reduced PKC function and expression, suggesting that the dysfunction was not primary linked to PKC signals. RNA-Seq analysis of PA revealed that the MT1R and MT2AR genes were significantly increased in the HS group, but their protein levels decreased. This suggests that MT receptors, rather than PKC signaling, are the key factors to influencing vascular contraction of PAs exposure to prenatal HS.
{"title":"Prenatal high-sucrose diet affects pulmonary artery contractile functions via MT receptors","authors":"Xueqin Feng , Hongwei Fu , Xiao Sun , Hua Shu , Yongning Zhu , Yanyan Bai , Qinggui Ren , Xinying Liu , Meng Liu , Fanyong Zhang , Yanping Wang","doi":"10.1016/j.reprotox.2024.108760","DOIUrl":"10.1016/j.reprotox.2024.108760","url":null,"abstract":"<div><div>A high sucrose diet during pregnancy may generate profound effects on vascular diseases in offspring later in life. Pulmonary artery (PA) functions is closely related to pulmonary hypertension, but whether and how prenatal high-sucrose diet (HS) affect pulmonary vasoreactivity in adult offspring remains unknown. We investigated the alterations of PA reactivity in postnatal offspring exposed to prenatal HS. Pregnant Sprague-Dawley rats were fed either a tap water or 20 % high sucrose solution throughout pregnancy. Pulmonary arteries from adult offspring were isolated and tested for all experiments. Prenatal HS increased vascular wall thickness, resulted in swollen mitochondria, and altered myofilament distribution in vascular smooth muscle layers of PA. Notably, the offspring's PAs from HS group showed increased vasoconstriction, but reduced PKC function and expression, suggesting that the dysfunction was not primary linked to PKC signals. RNA-Seq analysis of PA revealed that the MT1R and MT2AR genes were significantly increased in the HS group, but their protein levels decreased. This suggests that MT receptors, rather than PKC signaling, are the key factors to influencing vascular contraction of PAs exposure to prenatal HS.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108760"},"PeriodicalIF":3.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746674","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 : 2024-11-28DOI: 10.1016/j.reprotox.2024.108762
Hanwen Zhang, Yu Li, Na Li, Yilong Miao, Shaochen Sun, Ling Gu, Bo Xiong
Perfluorooctanoic acid (PFOA) exposure severely affects the health of animals and humans, including early embryonic development, but the effective approaches to improve the quality of embryos exposed to PFOA have not been explored. Here, we report that nicotinamide mononucleotide (NMN) can be used to attenuate the impairment of mouse early embryos caused by PFOA exposure. We find that NMN supplementation maintains the normal spindle assembly and proper chromosome alignment by restoring the acetylation level of microtubule to enhance the mitotic capacity of embryos at zygotic cleavage stage under PFOA exposure. In addition, NMN exerts its beneficial effect by enhancing mitochondrial function and eliminating accumulated reactive oxygen species (ROS), which in turn alleviates DNA damage and apoptosis in PFOA-exposed 2-cell embryos. Moreover, NMN ameliorates the quality of PFOA-exposed blastocysts via recovering the octamer-binding transcription factor 4 (Oct4) expression, the actin dynamics, and the total number of cells. Collectively, our findings demonstrate that supplementation with NMN is a feasible strategy to restore the compromised early embryonic development under PFOA exposure, providing a scientific basis for application of NMN to increase the female fertility.
{"title":"Nicotinamide mononucleotide enhances the developmental potential of mouse early embryos exposed to perfluorooctanoic acid","authors":"Hanwen Zhang, Yu Li, Na Li, Yilong Miao, Shaochen Sun, Ling Gu, Bo Xiong","doi":"10.1016/j.reprotox.2024.108762","DOIUrl":"10.1016/j.reprotox.2024.108762","url":null,"abstract":"<div><div>Perfluorooctanoic acid (PFOA) exposure severely affects the health of animals and humans, including early embryonic development, but the effective approaches to improve the quality of embryos exposed to PFOA have not been explored. Here, we report that nicotinamide mononucleotide (NMN) can be used to attenuate the impairment of mouse early embryos caused by PFOA exposure. We find that NMN supplementation maintains the normal spindle assembly and proper chromosome alignment by restoring the acetylation level of microtubule to enhance the mitotic capacity of embryos at zygotic cleavage stage under PFOA exposure. In addition, NMN exerts its beneficial effect by enhancing mitochondrial function and eliminating accumulated reactive oxygen species (ROS), which in turn alleviates DNA damage and apoptosis in PFOA-exposed 2-cell embryos. Moreover, NMN ameliorates the quality of PFOA-exposed blastocysts <em>via</em> recovering the octamer-binding transcription factor 4 (Oct4) expression, the actin dynamics, and the total number of cells. Collectively, our findings demonstrate that supplementation with NMN is a feasible strategy to restore the compromised early embryonic development under PFOA exposure, providing a scientific basis for application of NMN to increase the female fertility.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108762"},"PeriodicalIF":3.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746004","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 : 2024-11-28DOI: 10.1016/j.reprotox.2024.108758
Zishui Fang , Zirun Jin , Qiancheng Zhao , Jiaming Weng , Zhe Zhang , Yuzhuo Yang , Hui Jiang
Di-(2-ethylhexyl) phthalate (DEHP) exposure has been associated with male reproductive damage, but the mechanisms involved remain incompletely defined. This study aims to investigate the effects of DEHP exposure on the testes of prepubertal rats through an integrative analysis of metabolomics and transcriptomics, combined with molecular experiments. DEHP exposure resulted in decreased testis weight and increased oxidative stress level in the testis tissues of prepubertal male rats. Moreover, our findings showed a disordered testis structure, reduced spermatogenic and Sertoli cells as well as destruction of mitochondria structure in the testis tissues of DEHP-treated prepubertal male rats. Transcriptome function analysis together with metabolome function analysis indicated that spermatogenesis, apoptosis, inflammatory, lipid metabolism as well as DNA repair signaling pathway were enriched in the testis of DEHP-treated prepubertal male rats. The integrative omics analysis further suggested that TNF-α induced apoptosis played a crucial role in mediating the detrimental effects of DEHP exposure on the testis of prepubertal rats, which was validated by ELISA, Western blotting and Tunel assays. Validation experiments conducted in vitro using GC-2 cells corroborated these findings, demonstrating that mono-(2-ethylhexyl) phthalate (MEHP), the main active metabolite of DEHP, significantly inhibits cell proliferation and increases apoptosis via activating the TNF-α apoptosis pathway. Overall, these findings provided a novel mechanism of dysregulated spermatogenesis of DEHP exposure on the testes of prepubertal rats.
{"title":"Multi-omics revealed activation of TNF-α induced apoptosis signaling pathway in testis of DEHP treated prepubertal male rat","authors":"Zishui Fang , Zirun Jin , Qiancheng Zhao , Jiaming Weng , Zhe Zhang , Yuzhuo Yang , Hui Jiang","doi":"10.1016/j.reprotox.2024.108758","DOIUrl":"10.1016/j.reprotox.2024.108758","url":null,"abstract":"<div><div>Di-(2-ethylhexyl) phthalate (DEHP) exposure has been associated with male reproductive damage, but the mechanisms involved remain incompletely defined. This study aims to investigate the effects of DEHP exposure on the testes of prepubertal rats through an integrative analysis of metabolomics and transcriptomics, combined with molecular experiments. DEHP exposure resulted in decreased testis weight and increased oxidative stress level in the testis tissues of prepubertal male rats. Moreover, our findings showed a disordered testis structure, reduced spermatogenic and Sertoli cells as well as destruction of mitochondria structure in the testis tissues of DEHP-treated prepubertal male rats. Transcriptome function analysis together with metabolome function analysis indicated that spermatogenesis, apoptosis, inflammatory, lipid metabolism as well as DNA repair signaling pathway were enriched in the testis of DEHP-treated prepubertal male rats. The integrative omics analysis further suggested that TNF-α induced apoptosis played a crucial role in mediating the detrimental effects of DEHP exposure on the testis of prepubertal rats, which was validated by ELISA, Western blotting and Tunel assays. Validation experiments conducted <em>in vitro</em> using GC-2 cells corroborated these findings, demonstrating that mono-(2-ethylhexyl) phthalate (MEHP), the main active metabolite of DEHP, significantly inhibits cell proliferation and increases apoptosis via activating the TNF-α apoptosis pathway. Overall, these findings provided a novel mechanism of dysregulated spermatogenesis of DEHP exposure on the testes of prepubertal rats.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108758"},"PeriodicalIF":3.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755393","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 : 2024-11-23DOI: 10.1016/j.reprotox.2024.108754
C. Ben Lovely
Fetal Alcohol Spectrum Disorders (FASD) describes a wide array of neurological defects and craniofacial malformations, associated with ethanol teratogenicity. While there is growing evidence for a genetic component to FASD, little is known of the genes underlying these ethanol-induced defects. Along with timing and dosage, genetic predispositions may help explain the variability within FASD. From a screen for gene-ethanol interactions, we found that mutants for Bmp signaling components are ethanol-sensitive leading to defects in the zebrafish palate. Loss of Bmp signaling results in reductions in gata3 expression in the maxillary domain of the neural crest in the 1st pharyngeal arch, leading to palate defects while upregulation of human GATA3 rescues these defects. Here, we show that ethanol-treated Bmp mutants exhibit misshaped and/or broken trabeculae. Surprisingly, up regulation of GATA3 does not rescue ethanol-induced palate defects and gata3 expression was not altered in ethanol-treated Bmp mutants or dorsomorphin-treated larvae. Timing of ethanol sensitivity shows that Bmp mutants are ethanol sensitive from 10 to 18 hours post-fertilization (hpf), prior to Bmp’s regulation of gata3 in palate formation. This is consistent with our previous work with dorsomorphin-dependent knock down of Bmp signaling from 10 to 18 hpf disrupting endoderm formation and subsequent jaw development. Overall, this suggests that ethanol disrupts Bmp-dependent palate development independent of and earlier than the role of gata3 in palate formation by disrupting epithelial development. Ultimately, these data demonstrate that zebrafish is a useful model to identify and characterize gene-ethanol interactions and this work will directly inform our understanding of FASD.
{"title":"Bone morphogenetic protein signaling pathway– Ethanol interactions disrupt palate formation independent of gata3","authors":"C. Ben Lovely","doi":"10.1016/j.reprotox.2024.108754","DOIUrl":"10.1016/j.reprotox.2024.108754","url":null,"abstract":"<div><div>Fetal Alcohol Spectrum Disorders (FASD) describes a wide array of neurological defects and craniofacial malformations, associated with ethanol teratogenicity. While there is growing evidence for a genetic component to FASD, little is known of the genes underlying these ethanol-induced defects. Along with timing and dosage, genetic predispositions may help explain the variability within FASD. From a screen for gene-ethanol interactions, we found that mutants for Bmp signaling components are ethanol-sensitive leading to defects in the zebrafish palate. Loss of Bmp signaling results in reductions in <em>gata3</em> expression in the maxillary domain of the neural crest in the 1st pharyngeal arch, leading to palate defects while upregulation of human <em>GATA3</em> rescues these defects. Here, we show that ethanol-treated Bmp mutants exhibit misshaped and/or broken trabeculae. Surprisingly, up regulation of <em>GATA3</em> does not rescue ethanol-induced palate defects and <em>gata3</em> expression was not altered in ethanol-treated Bmp mutants or dorsomorphin-treated larvae. Timing of ethanol sensitivity shows that Bmp mutants are ethanol sensitive from 10 to 18 hours post-fertilization (hpf), prior to Bmp’s regulation of <em>gata3</em> in palate formation. This is consistent with our previous work with dorsomorphin-dependent knock down of Bmp signaling from 10 to 18 hpf disrupting endoderm formation and subsequent jaw development. Overall, this suggests that ethanol disrupts Bmp-dependent palate development independent of and earlier than the role of <em>gata3</em> in palate formation by disrupting epithelial development. Ultimately, these data demonstrate that zebrafish is a useful model to identify and characterize gene-ethanol interactions and this work will directly inform our understanding of FASD.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"131 ","pages":"Article 108754"},"PeriodicalIF":3.3,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717006","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 : 2024-11-22DOI: 10.1016/j.reprotox.2024.108752
Antje Munder, Christina Kloth, Geertje Lewin
The ECHA's work aims to establish uniform procedures for the authorization or restriction of the use of chemicals in the European Union. Studies conducted in accordance with OECD Guideline 443, in which, among others, the evaluation of pituitary and thyroid hormones and fertility under high-dose exposure are used as read-out parameters. Since 2022, ECHA has been compiling such extended one-generation reproductive toxicity (EOGRT) study data and publishing its assessments with regard to design, study conduct and toxicological results. Based on this, since then the authority has made demands on EOGRT study performers that are excessive, sometimes contra productive, may hamper data interpretation and lead neither to an improved validity of the studies nor to better animal welfare. Here, we explicitly address the physiological variability of pituitary hormone values and the interaction of reproductive toxicity with high dose exposure scenarios.
{"title":"Evaluation of reproductive toxicology studies according the OECD Guideline 443 – Claim and reality","authors":"Antje Munder, Christina Kloth, Geertje Lewin","doi":"10.1016/j.reprotox.2024.108752","DOIUrl":"10.1016/j.reprotox.2024.108752","url":null,"abstract":"<div><div>The ECHA's work aims to establish uniform procedures for the authorization or restriction of the use of chemicals in the European Union. Studies conducted in accordance with OECD Guideline 443, in which, among others, the evaluation of pituitary and thyroid hormones and fertility under high-dose exposure are used as read-out parameters. Since 2022, ECHA has been compiling such extended one-generation reproductive toxicity (EOGRT) study data and publishing its assessments with regard to design, study conduct and toxicological results. Based on this, since then the authority has made demands on EOGRT study performers that are excessive, sometimes contra productive, may hamper data interpretation and lead neither to an improved validity of the studies nor to better animal welfare. Here, we explicitly address the physiological variability of pituitary hormone values and the interaction of reproductive toxicity with high dose exposure scenarios.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108752"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695852","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 : 2024-11-22DOI: 10.1016/j.reprotox.2024.108755
Ana Flávia Quiarato Lozano , Isabella Cena Guimarães , Lucas Nicolás González , Patricia Sara Cuasnicu , Débora Juana Cohen , Wilma De Grava Kempinas
There are still few studies that have investigated the impact of sertraline (SE) on fertility, as well as adjuvant treatments that alleviate its side effects. Thus, the present study aimed to investigate the impact of SE on reproductive and neurobehavior parameters and verify whether the probiotic Lactobacillus rhamnosus alleviates the side effects of SE. After carrying out a dose-response study with SE, experiment II was conducted. Thus, male mice were distributed into four experimental groups (n=8–9/group): control (CO)-received filtered water (vehicle); sertraline group (S)–received 20 mg/kg of SE, diluted in the vehicle; probiotic (P)-received the probiotic Lactobacillus rhamnosus (1×109 CFU) diluted in the vehicle; and SP group that received both probiotic and SE. The treatment occurred/lasted for 30 days. At the end of treatment, behavioral aspects were analyzed. After euthanasia, the organs were weighed, the histology of the testis and epididymis were analyzed, and the sperm quality and also natural fertility were verified. Complementarily, in vitro assays were carried out to verify whether sertraline could affect sperm capacitation and embryonic development. The results showed that the SP group, compared to S, did not reduce body weight and seminal gland weight and presented a lower number of resorptions. Notably, the rate of resorption in both the SP and S groups was similar to that of the control group. It was also observed that the S group was less exploratory and more anxious than the SP group. Thus, the present study demonstrated that SE has an impact on the reproductive system and neurobehavior. Therefore, for the first time, we demonstrate that the probiotic can alleviate the side effects of SE.
关于舍曲林（SE）对生育能力的影响以及减轻其副作用的辅助治疗方法的研究仍然很少。因此，本研究旨在调查舍曲林对生殖和神经行为参数的影响，并验证鼠李糖乳杆菌益生菌是否能减轻舍曲林的副作用。在对 SE 进行剂量反应研究后，进行了实验 II。因此，雄性小鼠被分为四个实验组（n=8-9/组）：对照组（CO）--接受过滤水（载体）；舍曲林组（S）--接受稀释在载体中的 20 毫克/千克 SE；益生菌组（P）--接受稀释在载体中的益生菌鼠李糖乳杆菌（1×109 CFU）；以及同时接受益生菌和 SE 的 SP 组。治疗为期 30 天。治疗结束后，对动物的行为进行分析。安乐死后，对器官进行称重，分析睾丸和附睾的组织学，验证精子质量和自然受精能力。此外，还进行了体外试验，以验证舍曲林是否会影响精子获能和胚胎发育。结果表明，与 S 组相比，SP 组的体重和精液腺重量都没有减少，精子再获能的次数也较少。值得注意的是，SP 组和 S 组的精子吸收率与对照组相似。此外，还观察到 S 组比 SP 组更少探索和更焦虑。因此，本研究表明，SE 对生殖系统和神经行为有影响。因此，我们首次证明益生菌可以减轻 SE 的副作用。
{"title":"Could probiotics be used as a novel therapeutic approach to alleviate the reproductive and neurobehavioral side effects of sertraline? A study in male mice","authors":"Ana Flávia Quiarato Lozano , Isabella Cena Guimarães , Lucas Nicolás González , Patricia Sara Cuasnicu , Débora Juana Cohen , Wilma De Grava Kempinas","doi":"10.1016/j.reprotox.2024.108755","DOIUrl":"10.1016/j.reprotox.2024.108755","url":null,"abstract":"<div><div>There are still few studies that have investigated the impact of sertraline (SE) on fertility, as well as adjuvant treatments that alleviate its side effects. Thus, the present study aimed to investigate the impact of SE on reproductive and neurobehavior parameters and verify whether the probiotic <em>Lactobacillus rhamnosus</em> alleviates the side effects of SE. After carrying out a dose-response study with SE, experiment II was conducted. Thus, male mice were distributed into four experimental groups (n=8–9/group): control (CO)-received filtered water (vehicle); sertraline group (S)–received 20 mg/kg of SE, diluted in the vehicle; probiotic (P)-received the probiotic <em>Lactobacillus rhamnosus</em> (1×10<sup>9</sup> CFU) diluted in the vehicle; and SP group that received both probiotic and SE. The treatment occurred/lasted for 30 days. At the end of treatment, behavioral aspects were analyzed. After euthanasia, the organs were weighed, the histology of the testis and epididymis were analyzed, and the sperm quality and also natural fertility were verified. Complementarily, <em>in vitro</em> assays were carried out to verify whether sertraline could affect sperm capacitation and embryonic development. The results showed that the SP group, compared to S, did not reduce body weight and seminal gland weight and presented a lower number of resorptions. Notably, the rate of resorption in both the SP and S groups was similar to that of the control group. It was also observed that the S group was less exploratory and more anxious than the SP group. Thus, the present study demonstrated that SE has an impact on the reproductive system and neurobehavior. Therefore, for the first time, we demonstrate that the probiotic can alleviate the side effects of SE.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"131 ","pages":"Article 108755"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695809","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 : 2024-11-22DOI: 10.1016/j.reprotox.2024.108753
Giovanna Semino-Beninel , Stephanie Melching-Kollmuss , Simon Hill
The European Food Safety Authority (EFSA) conducted a retrospective cumulative dietary risk assessment (CRA) on active substances (AS) and metabolites included in the plant protection products registered in Europe which could provoke craniofacial alterations. Two Cumulative Assessment groups (CAGs) were established: one for alterations due to abnormal skeletal development (CAG-DAC) and one for head soft tissue alterations and brain neural tube defects (CAG-DAH). The probability that each substance is correctly assigned to the specific CAGs (CAG-membership probability) was assessed using weight of evidence and expert knowledge elicitation (EKE) techniques conducted for the six substances identified as risk drivers in each CAG. Four out of the six substances allocated to the CAG-DAC or to the CAG-DAH presented a large interval of uncertainty, with probability of belonging to the attributed CAG between 10 % and 70 % or 33–90 %, which makes it difficult to determine if the substances truly belong to the CAG. In the present work the probability ranges of each risk driver were reassigned according to the approximate probability scale recommended in the EFSA guidance on uncertainty analysis. It is proposed that AS with a high probability are to be included in the CAG and those with a low probability removed from the CAG. For compounds with very large probability ranges, uncertainty assessments would have to be redone to reach narrower probability ranges. Finally, whenever recent decisions on reproduction toxicity classifications made by the European Chemical Agency (ECHA) are available, these should be used to conclude on CAG memberships.
{"title":"Critical appraisal of the expert knowledge elicitation (EKE) methodology to identify uncertainties in building cumulative assessment groups for craniofacial alterations","authors":"Giovanna Semino-Beninel , Stephanie Melching-Kollmuss , Simon Hill","doi":"10.1016/j.reprotox.2024.108753","DOIUrl":"10.1016/j.reprotox.2024.108753","url":null,"abstract":"<div><div>The European Food Safety Authority (EFSA) conducted a retrospective cumulative dietary risk assessment (CRA) on active substances (AS) and metabolites included in the plant protection products registered in Europe which could provoke craniofacial alterations. Two Cumulative Assessment groups (CAGs) were established: one for alterations due to abnormal skeletal development (CAG-DAC) and one for head soft tissue alterations and brain neural tube defects (CAG-DAH). The probability that each substance is correctly assigned to the specific CAGs (CAG-membership probability) was assessed using weight of evidence and expert knowledge elicitation (EKE) techniques conducted for the six substances identified as risk drivers in each CAG. Four out of the six substances allocated to the CAG-DAC or to the CAG-DAH presented a large interval of uncertainty, with probability of belonging to the attributed CAG between 10 % and 70 % or 33–90 %, which makes it difficult to determine if the substances truly belong to the CAG. In the present work the probability ranges of each risk driver were reassigned according to the approximate probability scale recommended in the EFSA guidance on uncertainty analysis. It is proposed that AS with a high probability are to be included in the CAG and those with a low probability removed from the CAG. For compounds with very large probability ranges, uncertainty assessments would have to be redone to reach narrower probability ranges. Finally, whenever recent decisions on reproduction toxicity classifications made by the European Chemical Agency (ECHA) are available, these should be used to conclude on CAG memberships.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"132 ","pages":"Article 108753"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695819","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 : 2024-11-17DOI: 10.1016/j.reprotox.2024.108749
Yanggang Hong , Yi Wang , Deqi Wang , Qichao Yuan , Zihan Yang , Chuncao Deng
Environmental pollutants, especially endocrine-disrupting chemicals (EDCs) like di-ethylhexyl phthalate (DEHP), pose serious threats to human health, with DEHP widely implicated in male reproductive toxicity. However, the complex molecular interactions remain unknown. We employed a network toxicology approach combined with molecular docking analysis to identify potential targets and mechanisms of DEHP's toxic effects. Databases such as ChEMBL, STITCH, OMIM, and GeneCards were utilized to gather data, and Cytoscape software was used to construct protein-protein interaction networks. A total of 51 potential targets were identified, with eight core targets, including PTGS2, CASP3, and ESR1, highlighted for their roles in oxidative stress, apoptosis, and hormonal dysregulation. KEGG pathway enrichment analysis revealed significant associations with pathways in cancer, cytokine-mediated signaling, and the hypothalamic-pituitary-gonadal axis. Additionally, gene expression datasets from the Gene Expression Omnibus (GEO) database were analyzed to identify differentially expressed genes overlapped with DEHP targets in testicular diseases. Molecular docking results confirmed strong binding affinities between DEHP and the core target proteins, suggesting a robust interaction mechanism. This study underscores the need for further investigation into DEHP's toxic mechanisms and its combined effects with other environmental pollutants, paving the way for comprehensive risk assessments and the development of targeted intervention strategies.
{"title":"Assessing male reproductive toxicity of environmental pollutant di-ethylhexyl phthalate with network toxicology and molecular docking strategy","authors":"Yanggang Hong , Yi Wang , Deqi Wang , Qichao Yuan , Zihan Yang , Chuncao Deng","doi":"10.1016/j.reprotox.2024.108749","DOIUrl":"10.1016/j.reprotox.2024.108749","url":null,"abstract":"<div><div>Environmental pollutants, especially endocrine-disrupting chemicals (EDCs) like di-ethylhexyl phthalate (DEHP), pose serious threats to human health, with DEHP widely implicated in male reproductive toxicity. However, the complex molecular interactions remain unknown. We employed a network toxicology approach combined with molecular docking analysis to identify potential targets and mechanisms of DEHP's toxic effects. Databases such as ChEMBL, STITCH, OMIM, and GeneCards were utilized to gather data, and Cytoscape software was used to construct protein-protein interaction networks. A total of 51 potential targets were identified, with eight core targets, including PTGS2, CASP3, and ESR1, highlighted for their roles in oxidative stress, apoptosis, and hormonal dysregulation. KEGG pathway enrichment analysis revealed significant associations with pathways in cancer, cytokine-mediated signaling, and the hypothalamic-pituitary-gonadal axis. Additionally, gene expression datasets from the Gene Expression Omnibus (GEO) database were analyzed to identify differentially expressed genes overlapped with DEHP targets in testicular diseases. Molecular docking results confirmed strong binding affinities between DEHP and the core target proteins, suggesting a robust interaction mechanism. This study underscores the need for further investigation into DEHP's toxic mechanisms and its combined effects with other environmental pollutants, paving the way for comprehensive risk assessments and the development of targeted intervention strategies.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"130 ","pages":"Article 108749"},"PeriodicalIF":3.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646655","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 : 2024-11-16DOI: 10.1016/j.reprotox.2024.108746
Pallavi Singh , Priyanka Agrawal , K.P. Singh
Depression in pregnant women raises concerns about the safety of antidepressants use, particularly its impact on offspring’s neurocognition. This study investigates the effects of maternal exposure to vortioxetine (VOX) on the neurocognitive development of rat offspring. Pregnant Wistar rats were administered clinically pertinent doses of VOX, 1 mg/kg/day or 2 mg/kg/day from gestational day 6–21. The dams delivered their offspring naturally and reared until postnatal day (PND) 70. Offspring of both sexes were assessed for postnatal growth by measuring body weight from PND 1–70 weekly and cognitive function using Morris water maze (MWM) test and passive avoidance learning test from PND 49–70. After behavioral assessments, adult rat offspring were sacrificed, and their brains were dissected out for assessment of brain morphology as well as biochemical analysis. The results demonstrated that VOX exposure potentially impaired cognitive performance, evidenced by increased latency in MWM and passive avoidance learning tests. Additionally, it led to decreased body weight, altered brain morphology, and disrupted neurobiochemical profiles. Specifically, VOX 2 mg/kg exposure significantly reduced brain-derived neurotrophic factor (BDNF) expression, increased pro-apoptotic BAX expression, decreased anti-apoptotic Bcl-2 expression, and elevated acetylcholinesterase (AChE) activity in the hippocampus. Lower dose of VOX (1 mg/kg) did not show significant adverse effects on neurocognition, suggesting a dose-dependent impact. No sex specific neurocognitive deficits were observed in current study. These findings indicate that while VOX may offer a safer profile compared to SSRIs, high doses during pregnancy can still result in neurocognitive impairments in offspring.
{"title":"Neurocognitive impairments in rat offspring after maternal exposure to vortioxetine: Involvement of BDNF, apoptosis and cholinergic mediated signaling pathways","authors":"Pallavi Singh , Priyanka Agrawal , K.P. Singh","doi":"10.1016/j.reprotox.2024.108746","DOIUrl":"10.1016/j.reprotox.2024.108746","url":null,"abstract":"<div><div>Depression in pregnant women raises concerns about the safety of antidepressants use, particularly its impact on offspring’s neurocognition. This study investigates the effects of maternal exposure to vortioxetine (VOX) on the neurocognitive development of rat offspring. Pregnant Wistar rats were administered clinically pertinent doses of VOX, 1 mg/kg/day or 2 mg/kg/day from gestational day 6–21. The dams delivered their offspring naturally and reared until postnatal day (PND) 70. Offspring of both sexes were assessed for postnatal growth by measuring body weight from PND 1–70 weekly and cognitive function using Morris water maze (MWM) test and passive avoidance learning test from PND 49–70. After behavioral assessments, adult rat offspring were sacrificed, and their brains were dissected out for assessment of brain morphology as well as biochemical analysis. The results demonstrated that VOX exposure potentially impaired cognitive performance, evidenced by increased latency in MWM and passive avoidance learning tests. Additionally, it led to decreased body weight, altered brain morphology, and disrupted neurobiochemical profiles. Specifically, VOX 2 mg/kg exposure significantly reduced brain-derived neurotrophic factor (BDNF) expression, increased pro-apoptotic BAX expression, decreased anti-apoptotic Bcl-2 expression, and elevated acetylcholinesterase (AChE) activity in the hippocampus. Lower dose of VOX (1 mg/kg) did not show significant adverse effects on neurocognition, suggesting a dose-dependent impact. No sex specific neurocognitive deficits were observed in current study. These findings indicate that while VOX may offer a safer profile compared to SSRIs, high doses during pregnancy can still result in neurocognitive impairments in offspring.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"131 ","pages":"Article 108746"},"PeriodicalIF":3.3,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668928","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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