Pub Date : 2024-06-27DOI: 10.1016/j.reprotox.2024.108633
3-chloro-1,2-propanediol (3-MCPD) is a newly discovered food process pollutant with nephrotoxicity. And the mechanism by which 3-MCPD affects male spermatogenesis has not been fully studied. Cell viability, blood-testis barrier (BTB) related protein, progesterone content, reactive oxygen species (ROS) generation, and cell apoptosis were determined by a CCK8 assay, western blot, ELISA, flow cytometry, and TUNEL staining, respectively. Wistar rats were divided into three groups: low-dose 3-MCPD, high-dose 3-MCPD, and control. Sperm parameters, hormonal levels, and biomarkers of oxidative stress in the testis and epididymis were detected by ELISA. Multiple molecular experiments including molecular docking and western blot were used to elucidate the underlying mechanisms. 3-MCPD affects testicular cell activity, and promotes ROS production and apoptosis. Disrupting the integrity of BTB in the body, downregulating sex hormones and sperm quality, and promoting apoptosis. 3-MCPD may function through CYP2C9. This study preliminarily explores the mechanism by which 3-MCPD affects spermatogenesis. It was found that 3-MCPD destroys the structure and function of BTB and damages the testicular function of male mice, thus affecting the process of spermatogenesis via CYP2C9.
{"title":"3-chloro-1,2-propanediol induces oxidative stress and promotes testicular damage and infertility in rats through CYP2C9","authors":"","doi":"10.1016/j.reprotox.2024.108633","DOIUrl":"10.1016/j.reprotox.2024.108633","url":null,"abstract":"<div><p>3-chloro-1,2-propanediol (3-MCPD) is a newly discovered food process pollutant with nephrotoxicity. And the mechanism by which 3-MCPD affects male spermatogenesis has not been fully studied. Cell viability, blood-testis barrier (BTB) related protein, progesterone content, reactive oxygen species (ROS) generation, and cell apoptosis were determined by a CCK8 assay, western blot, ELISA, flow cytometry, and TUNEL staining, respectively. Wistar rats were divided into three groups: low-dose 3-MCPD, high-dose 3-MCPD, and control. Sperm parameters, hormonal levels, and biomarkers of oxidative stress in the testis and epididymis were detected by ELISA. Multiple molecular experiments including molecular docking and western blot were used to elucidate the underlying mechanisms. 3-MCPD affects testicular cell activity, and promotes ROS production and apoptosis. Disrupting the integrity of BTB in the body, downregulating sex hormones and sperm quality, and promoting apoptosis. 3-MCPD may function through CYP2C9. This study preliminarily explores the mechanism by which 3-MCPD affects spermatogenesis. It was found that 3-MCPD destroys the structure and function of BTB and damages the testicular function of male mice, thus affecting the process of spermatogenesis via CYP2C9.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S089062382400100X/pdfft?md5=5b0a78b252346f78cff851e6fed39039&pid=1-s2.0-S089062382400100X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470500","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 : 2024-06-26DOI: 10.1016/j.reprotox.2024.108635
Natalia P. Silva , Charles S. da Costa , Kayke L. Barbosa , Cidália de F. Januario , Leticia N. Gama-de-Souza , Cinthia Breves , Rodrigo S. Fortunato , Leandro Miranda-Alves , Miriane de Oliveira , Celia R. Nogueira , Jones B. Graceli
Tributyltin (TBT) is an endocrine-disrupting chemical (EDC) related to reproductive dysfunctions. However, few studies have investigated the effects of TBT exposure on mammary gland development. Thus, we assessed whether subacute TBT exposure causes irregularities in mammary gland development. We administered TBT (100 and 1,000 ng/kg/day for 30 days) to female rats from postnatal day (PND) 25 to PND 55, and mammary gland development, morphology, inflammation, collagen deposition, and protein expression were evaluated. Abnormal mammary gland development was observed in both TBT groups. Specifically, TBT exposure reduced the number of terminal end buds (TEBs), type 1 (AB1) alveolar buds, and type 2 (AB2) alveolar buds. An increase in the lobule and differentiation (DF) 2 score was found in the mammary glands of TBT rats. TBT exposure increased mammary gland blood vessels, mast cell numbers, and collagen deposition. Additionally, both TBT rats exhibited intraductal hyperplasia and TEB-like structures. An increase in estrogen receptor alpha (ERα), progesterone receptor (PR), and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) - positive cells was observed in the mammary glands of TBT rats. A strong negative correlation was observed between CYP19A1- positive cells and TEB number. In addition, CYP19A1 - positive cells were positively correlated with mammary gland TEB-like structure, ductal hyperplasia, inflammation, and collagen deposition. Thus, these data suggest that TBT exposure impairs mammary gland development through the modulation of CYP19A1 signaling pathways in female rats.
{"title":"Subacute tributyltin exposure alters the development and morphology of mammary glands in association with CYP19A1 expression in female rats","authors":"Natalia P. Silva , Charles S. da Costa , Kayke L. Barbosa , Cidália de F. Januario , Leticia N. Gama-de-Souza , Cinthia Breves , Rodrigo S. Fortunato , Leandro Miranda-Alves , Miriane de Oliveira , Celia R. Nogueira , Jones B. Graceli","doi":"10.1016/j.reprotox.2024.108635","DOIUrl":"10.1016/j.reprotox.2024.108635","url":null,"abstract":"<div><p>Tributyltin (TBT) is an endocrine-disrupting chemical (EDC) related to reproductive dysfunctions. However, few studies have investigated the effects of TBT exposure on mammary gland development. Thus, we assessed whether subacute TBT exposure causes irregularities in mammary gland development. We administered TBT (100 and 1,000 ng/kg/day for 30 days) to female rats from postnatal day (PND) 25 to PND 55, and mammary gland development, morphology, inflammation, collagen deposition, and protein expression were evaluated. Abnormal mammary gland development was observed in both TBT groups. Specifically, TBT exposure reduced the number of terminal end buds (TEBs), type 1 (AB1) alveolar buds, and type 2 (AB2) alveolar buds. An increase in the lobule and differentiation (DF) 2 score was found in the mammary glands of TBT rats. TBT exposure increased mammary gland blood vessels, mast cell numbers, and collagen deposition. Additionally, both TBT rats exhibited intraductal hyperplasia and TEB-like structures. An increase in estrogen receptor alpha (ERα), progesterone receptor (PR), and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) - positive cells was observed in the mammary glands of TBT rats. A strong negative correlation was observed between CYP19A1- positive cells and TEB number. In addition, CYP19A1 - positive cells were positively correlated with mammary gland TEB-like structure, ductal hyperplasia, inflammation, and collagen deposition. Thus, these data suggest that TBT exposure impairs mammary gland development through the modulation of CYP19A1 signaling pathways in female rats.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470503","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 : 2024-06-26DOI: 10.1016/j.reprotox.2024.108649
Linda Schenk , Meng-Rung Ho , Piia Taxell , Pasi Huuskonen , Mimmi Leite , Inese Martinsone , Karl-Christian Nordby , Linda Paegle , Loreta Strumylaite
We investigated the level of protection of reproductive and developmental toxicity offered through occupational exposure limits (OELs) and Derived No-Effect Levels for workers’ inhalation exposure (wDNELs). We compared coverage of substances that have a harmonised classification as reproductive toxicant 1 A or 1B (Repr.1 A/B), numerical values and scientific basis of 12 lists of OELs and wDNELs from REACH Registrants’ and the Committee for Risk Assessment. Across the 14 sources of OELs and wDNELs, 53 % of the Repr1A/B-substances had at least one exposure limit (counting groups of metals as one entry). Registrants’ wDNELs covered the largest share, 40 %. The numerical values could be highly variable for the same substance across the lists. How often reproductive toxicity is identified as the critical effect varies between the examined lists, both due to different assessments of the same substance and different substance coverage. Reviewing the margin of safety to reproductive toxicity cited in the documents, we found that 15 % of safety margins were lower to reproductive toxicity than the critical effect. To conclude, neither the REACH nor work environment legislation supply wDNELs or OELs for a substantial share of known reproductive toxicants. EU OELs cover among the fewest substances in the range, and in many cases national OELs or wDNELs are set at more conservative levels.
{"title":"Occupational exposure limits for reproductive toxicants – A comparative analysis","authors":"Linda Schenk , Meng-Rung Ho , Piia Taxell , Pasi Huuskonen , Mimmi Leite , Inese Martinsone , Karl-Christian Nordby , Linda Paegle , Loreta Strumylaite","doi":"10.1016/j.reprotox.2024.108649","DOIUrl":"10.1016/j.reprotox.2024.108649","url":null,"abstract":"<div><p>We investigated the level of protection of reproductive and developmental toxicity offered through occupational exposure limits (OELs) and Derived No-Effect Levels for workers’ inhalation exposure (wDNELs). We compared coverage of substances that have a harmonised classification as reproductive toxicant 1 A or 1B (Repr.1 A/B), numerical values and scientific basis of 12 lists of OELs and wDNELs from REACH Registrants’ and the Committee for Risk Assessment. Across the 14 sources of OELs and wDNELs, 53 % of the Repr1A/B-substances had at least one exposure limit (counting groups of metals as one entry). Registrants’ wDNELs covered the largest share, 40 %. The numerical values could be highly variable for the same substance across the lists. How often reproductive toxicity is identified as the critical effect varies between the examined lists, both due to different assessments of the same substance and different substance coverage. Reviewing the margin of safety to reproductive toxicity cited in the documents, we found that 15 % of safety margins were lower to reproductive toxicity than the critical effect. To conclude, neither the REACH nor work environment legislation supply wDNELs or OELs for a substantial share of known reproductive toxicants. EU OELs cover among the fewest substances in the range, and in many cases national OELs or wDNELs are set at more conservative levels.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0890623824001163/pdfft?md5=b53065ede8a7e776d840d6db6f733e9a&pid=1-s2.0-S0890623824001163-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470502","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 : 2024-06-24DOI: 10.1016/j.reprotox.2024.108651
Ola S. Davis , Olivia L.M. Scandlan , Reem Sabry , Mahta Ghaffarzadeh , Thomas G. Hannam , Alexander Lagunov , Laura A. Favetta
Bisphenol A (BPA) is a widespread industrial chemical, used as the key monomer of polycarbonate plastics and epoxy resins. BPA has been detected in human seminal fluid and has been correlated with changes in sperm parameters, crucial in determining male fertility. In this study, semen samples were collected from 100 patients aged 29–47 years undergoing fertility assessment between 2021 and 2023 and analyzed according to WHO guidelines. BPA levels in the seminal plasma were then measured through an enzyme-linked immunosorbent assay (ELISA) and compared to sperm quality metrics. The relative mRNA/miRNA expression of key genes associated to male reproduction, including androgen receptor, miR-34c, miR-21, miR-130a, was then quantified and compared between groups with high or low BPA content. Our results revealed that BPA levels were increased with age and were negatively correlated with sperm counts (p<0.05). The negative correlation remained significant when patients were age-matched. No other relationships between seminal BPA and motility, morphology or DNA fragmentation levels were observed. qPCR analysis showed that androgen receptor mRNA expression was significantly greater in sperm with high seminal BPA (p<0.05). Moreover, we found that the expression of miR-21 and miR-130a was also upregulated in the higher BPA group (p<0.05). These results display a relationship between BPA content in the semen and male fertility parameters, and provide insights into the molecular mechanisms through which BPA may be affecting male reproductive capability. Ultimately, this research can potentially drive changes to guidelines and exposure limits for BPA exposure.
双酚 A(BPA)是一种广泛使用的工业化学品,是聚碳酸酯塑料和环氧树脂的主要单体。人类精液中已检测到双酚 A,并与精子参数的变化有关,而精子参数是决定男性生育能力的关键。本研究收集了 100 名在 2021 年至 2023 年期间接受生育力评估的 29-47 岁患者的精液样本,并根据世卫组织指南进行了分析。然后通过酶联免疫吸附试验(ELISA)测定精浆中的双酚 A 水平,并与精子质量指标进行比较。然后对与男性生殖相关的关键基因(包括雄激素受体、miR-34c、miR-21、miR-130a)的相对 mRNA/miRNA 表达进行量化,并在双酚 A 含量高或低的组别之间进行比较。结果显示,双酚 A 含量随年龄增长而增加,并与精子数量呈负相关(p
{"title":"High seminal BPA in IVF patients correlates with lower sperm count and up-regulated miR-21 and miR-130a","authors":"Ola S. Davis , Olivia L.M. Scandlan , Reem Sabry , Mahta Ghaffarzadeh , Thomas G. Hannam , Alexander Lagunov , Laura A. Favetta","doi":"10.1016/j.reprotox.2024.108651","DOIUrl":"10.1016/j.reprotox.2024.108651","url":null,"abstract":"<div><p>Bisphenol A (BPA) is a widespread industrial chemical, used as the key monomer of polycarbonate plastics and epoxy resins. BPA has been detected in human seminal fluid and has been correlated with changes in sperm parameters, crucial in determining male fertility. In this study, semen samples were collected from 100 patients aged 29–47 years undergoing fertility assessment between 2021 and 2023 and analyzed according to WHO guidelines. BPA levels in the seminal plasma were then measured through an enzyme-linked immunosorbent assay (ELISA) and compared to sperm quality metrics. The relative mRNA/miRNA expression of key genes associated to male reproduction, including androgen receptor, miR-34c, miR-21, miR-130a, was then quantified and compared between groups with high or low BPA content. Our results revealed that BPA levels were increased with age and were negatively correlated with sperm counts (p<0.05). The negative correlation remained significant when patients were age-matched. No other relationships between seminal BPA and motility, morphology or DNA fragmentation levels were observed. qPCR analysis showed that androgen receptor mRNA expression was significantly greater in sperm with high seminal BPA (p<0.05). Moreover, we found that the expression of miR-21 and miR-130a was also upregulated in the higher BPA group (p<0.05). These results display a relationship between BPA content in the semen and male fertility parameters, and provide insights into the molecular mechanisms through which BPA may be affecting male reproductive capability. Ultimately, this research can potentially drive changes to guidelines and exposure limits for BPA exposure.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0890623824001187/pdfft?md5=9e4f3649d06ff3121d80363073d98028&pid=1-s2.0-S0890623824001187-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141459015","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 : 2024-06-22DOI: 10.1016/j.reprotox.2024.108647
John L.P. Coimbra , Gabriel Campolina-Silva , Daniel F. Lair , Luiz O. Guimarães-Ervilha , Ana C.F. Souza , Cleida A. Oliveira , Guilherme M.J. Costa , Mariana Machado-Neves
The prostate gland is one of the main sites of hyperplasia and cancer in elderly men. Numerous factors have been demonstrated to disrupt prostate homeostasis, including exposure to environmental pollutants. Arsenic is a metalloid found ubiquitously in soil, air, and water, which favors human poisoning through the involuntary intake of contaminated drinking water and food and has harmful effects by increasing the oxidative stress response. This study aimed to investigate the effects of prolonged exposure to arsenic at environmentally relevant concentrations on the prostate biology of adult Wistar rats. Thirty 80-day-old male rats were divided into three experimental groups. Rats from the control group received filtered water, whereas animals from the arsenic groups ingested 1 mg L−1 and 10 mg L−1 of arsenic, in the form of sodium arsenite, daily. The arsenic solutions were provided ad libitum in the drinking water for eight weeks. Our results showed that 1 mg L−1 and 10 mg L−1 of arsenic made the prostate susceptible to evolving benign and premalignant histopathological changes. While the ingestion of 1 mg L−1 of arsenic reduced SOD activity only, 10 mg L−1 diminished SOD and CAT activity in the prostate tissue, culminating in high MDA production. These doses, however, did not affect the intraprostatic levels of DHT and estradiol. In conclusion, exposure to arsenic at environmentally relevant concentrations through drinking water induces histological and oxidative stress-related changes in the prostate of adult rats, strengthening the between arsenic exposure and prostate disorders.
{"title":"Subchronic intake of arsenic at environmentally relevant concentrations causes histological lesions and oxidative stress in the prostate of adult Wistar rats","authors":"John L.P. Coimbra , Gabriel Campolina-Silva , Daniel F. Lair , Luiz O. Guimarães-Ervilha , Ana C.F. Souza , Cleida A. Oliveira , Guilherme M.J. Costa , Mariana Machado-Neves","doi":"10.1016/j.reprotox.2024.108647","DOIUrl":"10.1016/j.reprotox.2024.108647","url":null,"abstract":"<div><p>The prostate gland is one of the main sites of hyperplasia and cancer in elderly men. Numerous factors have been demonstrated to disrupt prostate homeostasis, including exposure to environmental pollutants. Arsenic is a metalloid found ubiquitously in soil, air, and water, which favors human poisoning through the involuntary intake of contaminated drinking water and food and has harmful effects by increasing the oxidative stress response. This study aimed to investigate the effects of prolonged exposure to arsenic at environmentally relevant concentrations on the prostate biology of adult Wistar rats. Thirty 80-day-old male rats were divided into three experimental groups. Rats from the control group received filtered water, whereas animals from the arsenic groups ingested 1 mg L<sup>−1</sup> and 10 mg L<sup>−1</sup> of arsenic, in the form of sodium arsenite, daily. The arsenic solutions were provided <em>ad libitum</em> in the drinking water for eight weeks. Our results showed that 1 mg L<sup>−1</sup> and 10 mg L<sup>−1</sup> of arsenic made the prostate susceptible to evolving benign and premalignant histopathological changes. While the ingestion of 1 mg L<sup>−1</sup> of arsenic reduced SOD activity only, 10 mg L<sup>−1</sup> diminished SOD and CAT activity in the prostate tissue, culminating in high MDA production. These doses, however, did not affect the intraprostatic levels of DHT and estradiol. In conclusion, exposure to arsenic at environmentally relevant concentrations through drinking water induces histological and oxidative stress-related changes in the prostate of adult rats, strengthening the between arsenic exposure and prostate disorders.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141443219","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 : 2024-06-22DOI: 10.1016/j.reprotox.2024.108648
Yuanyuan Zhou , Fenglei Ye , Linyun Zhang , Quanmin Kang , Yujia Luo , Nan Jiang , Lijun Lou , Yuchan Mao , Liya Wang , Fan Jin
Previous retrospective cohort studies have found that, compared with oxygen tension in the uterus and fallopian tubes (2 %-8 %), exposure of pre-implantation embryos to atmospheric oxygen tension (AtmO2, 20 %) during assisted reproductive technology(ART) can affect embryo quality, pregnancy outcomes and offspring health. However, current research on the effects and mechanisms of AtmO2 on the development of embryos and offspring is mainly limited to animal experiments. Human embryonic stem cells (hESCs) play a special and irreplaceable role in the study of early human embryonic development. In this study, we used hESCs as a model to elucidate the possible effects and mechanisms of AtmO2 exposure on human embryonic development. We found that exposure to AtmO2 can reduce cell viability, produce oxidative stress, increase DNA damage, initiate DNA repair, activate autophagy, and increase cell apoptosis. We also noticed that approximately 50 % of hESCs survived, adapted and proliferated through high expression of self-renewal and pluripotency regulatory factors, and affected embryoid body differentiation. These data indicate that hESCs experience oxidative stress, accumulation of DNA damage, and activate DNA damage response under the selective pressure of AtmO2.Some hESCs undergo cell death, whereas other hESCs adapt and proliferate through increased expression of self-renewal genes. The current findings provide in vitro evidence that exposure to AtmO2 during the early preimplantation stage negatively affects hESCs.
以往的回顾性队列研究发现,与子宫和输卵管中的氧张力(2%-8%)相比,在辅助生殖技术(ART)过程中,植入前胚胎暴露于大气氧张力(AtmO2,20%)会影响胚胎质量、妊娠结局和后代健康。然而,目前有关 AtmO2 对胚胎和后代发育的影响和机制的研究主要局限于动物实验。人类胚胎干细胞(hESCs)在人类早期胚胎发育研究中发挥着不可替代的特殊作用。在本研究中,我们以 hESCs 为模型,阐明了暴露于 AtmO2 对人类胚胎发育可能产生的影响和机制。我们发现,暴露于 AtmO2 会降低细胞活力、产生氧化应激、增加 DNA 损伤、启动 DNA 修复、激活自噬和增加细胞凋亡。我们还注意到,约 50% 的 hESCs 通过高表达自我更新和多能性调控因子而存活、适应和增殖,并影响胚状体分化。这些数据表明,在 AtmO2 的选择性压力下,hESCs 会经历氧化应激、DNA 损伤积累并激活 DNA 损伤应答。目前的研究结果提供了体外证据,证明在植入前早期暴露于AtmO2会对hESC产生负面影响。
{"title":"The role of DNA damage response in human embryonic stem cells exposed to atmospheric oxygen tension: Implications for embryo development and differentiation","authors":"Yuanyuan Zhou , Fenglei Ye , Linyun Zhang , Quanmin Kang , Yujia Luo , Nan Jiang , Lijun Lou , Yuchan Mao , Liya Wang , Fan Jin","doi":"10.1016/j.reprotox.2024.108648","DOIUrl":"10.1016/j.reprotox.2024.108648","url":null,"abstract":"<div><p>Previous retrospective cohort studies have found that, compared with oxygen tension in the uterus and fallopian tubes (2 %-8 %), exposure of pre-implantation embryos to atmospheric oxygen tension (AtmO<sub>2</sub>, 20 %) during assisted reproductive technology(ART) can affect embryo quality, pregnancy outcomes and offspring health. However, current research on the effects and mechanisms of AtmO<sub>2</sub> on the development of embryos and offspring is mainly limited to animal experiments. Human embryonic stem cells (hESCs) play a special and irreplaceable role in the study of early human embryonic development. In this study, we used hESCs as a model to elucidate the possible effects and mechanisms of AtmO<sub>2</sub> exposure on human embryonic development. We found that exposure to AtmO<sub>2</sub> can reduce cell viability, produce oxidative stress, increase DNA damage, initiate DNA repair, activate autophagy, and increase cell apoptosis. We also noticed that approximately 50 % of hESCs survived, adapted and proliferated through high expression of self-renewal and pluripotency regulatory factors, and affected embryoid body differentiation. These data indicate that hESCs experience oxidative stress, accumulation of DNA damage, and activate DNA damage response under the selective pressure of AtmO<sub>2</sub>.Some hESCs undergo cell death, whereas other hESCs adapt and proliferate through increased expression of self-renewal genes. The current findings provide in vitro evidence that exposure to AtmO<sub>2</sub> during the early preimplantation stage negatively affects hESCs.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0890623824001151/pdfft?md5=d36a8d08e2023ee9015c0c027b8e3b81&pid=1-s2.0-S0890623824001151-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141443220","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 : 2024-06-19DOI: 10.1016/j.reprotox.2024.108630
Ravinder Kumar , Ashwini Oke , Beth Rockmill , Matthew de Cruz , Rafael Verduzco , Anura Shodhan , Xavier Woodruff-Madeira , Dimitri P. Abrahamsson , Julia Varshavsky , Juleen Lam , Joshua F. Robinson , Patrick Allard , Tracey J. Woodruff , Jennifer C. Fung
Infertility affects ∼12 % of couples, with environmental chemical exposure as a potential contributor. Of the chemicals that are actively manufactured, very few are assessed for reproductive health effects. Rodents are commonly used to evaluate reproductive effects, which is both costly and time consuming. Thus, there is a pressing need for rapid methods to test a broader range of chemicals. Here, we developed a strategy to evaluate large numbers of chemicals for reproductive toxicity via a yeast, S. cerevisiae high-throughput assay to assess gametogenesis as a potential new approach method (NAM). By simultaneously assessing chemicals for growth effects, we can distinguish if a chemical affects gametogenesis only, proliferative growth only or both. We identified a well-known mammalian reproductive toxicant, bisphenol A (BPA) and ranked 19 BPA analogs for reproductive harm. By testing mixtures of BPA and its analogs, we found that BPE and 17 β-estradiol each together with BPA showed synergistic effects that worsened reproductive outcome. We examined an additional 179 environmental chemicals including phthalates, pesticides, quaternary ammonium compounds and per- and polyfluoroalkyl substances and found 57 with reproductive effects. Many of the chemicals were found to be strong reproductive toxicants that have yet to be tested in mammals. Chemicals having affect before meiosis I division vs. meiosis II division were identified for 16 gametogenesis-specific chemicals. Finally, we demonstrate that in general yeast reproductive toxicity correlates well with published reproductive toxicity in mammals illustrating the promise of this NAM to quickly assess chemicals to prioritize the evaluation for human reproductive harm.
不孕症影响着约 12% 的夫妇,环境中的化学品暴露是潜在的诱因之一。在目前生产的化学品中,很少有化学品会对生殖健康产生影响。通常使用啮齿动物来评估对生殖的影响,这既昂贵又耗时。因此,我们迫切需要快速方法来检测更广泛的化学品。在此,我们开发了一种策略,通过酵母菌(S. cerevisiae)高通量试验来评估大量化学品的生殖毒性,从而评估配子的发生,将其作为一种潜在的新方法(NAM)。通过同时评估化学物质对生长的影响,我们可以区分某种化学物质是只影响配子发生,还是只影响增殖生长,抑或是两者兼而有之。我们确定了一种众所周知的哺乳动物生殖毒性物质--双酚 A(BPA),并对 19 种双酚 A 类似物的生殖危害进行了排名。通过测试双酚 A 及其类似物的混合物,我们发现 BPE 和 17 β-雌二醇与双酚 A 在一起会产生协同效应,导致生殖结果恶化。我们还研究了另外 179 种环境化学物质,包括邻苯二甲酸盐、杀虫剂、季铵化合物以及全氟和多氟烷基物质,发现其中 57 种对生殖有影响。发现其中许多化学物质具有强烈的生殖毒性,但尚未在哺乳动物体内进行测试。在减数分裂 I 分裂与减数分裂 II 分裂之前,我们发现了 16 种对配子发生有特异性影响的化学物质。最后,我们证明,一般来说,酵母的生殖毒性与已公布的哺乳动物生殖毒性有很好的相关性,这说明这种 NAM 可以快速评估化学品,优先评估其对人类生殖的危害。
{"title":"Rapid identification of reproductive toxicants among environmental chemicals using an in vivo evaluation of gametogenesis in budding yeast Saccharomyces cerevisiae","authors":"Ravinder Kumar , Ashwini Oke , Beth Rockmill , Matthew de Cruz , Rafael Verduzco , Anura Shodhan , Xavier Woodruff-Madeira , Dimitri P. Abrahamsson , Julia Varshavsky , Juleen Lam , Joshua F. Robinson , Patrick Allard , Tracey J. Woodruff , Jennifer C. Fung","doi":"10.1016/j.reprotox.2024.108630","DOIUrl":"10.1016/j.reprotox.2024.108630","url":null,"abstract":"<div><p>Infertility affects ∼12 % of couples, with environmental chemical exposure as a potential contributor. Of the chemicals that are actively manufactured, very few are assessed for reproductive health effects. Rodents are commonly used to evaluate reproductive effects, which is both costly and time consuming. Thus, there is a pressing need for rapid methods to test a broader range of chemicals. Here, we developed a strategy to evaluate large numbers of chemicals for reproductive toxicity via a yeast, <em>S. cerevisiae</em> high-throughput assay to assess gametogenesis as a potential new approach method (NAM). By simultaneously assessing chemicals for growth effects, we can distinguish if a chemical affects gametogenesis only, proliferative growth only or both. We identified a well-known mammalian reproductive toxicant, bisphenol A (BPA) and ranked 19 BPA analogs for reproductive harm. By testing mixtures of BPA and its analogs, we found that BPE and 17 β-estradiol each together with BPA showed synergistic effects that worsened reproductive outcome. We examined an additional 179 environmental chemicals including phthalates, pesticides, quaternary ammonium compounds and per- and polyfluoroalkyl substances and found 57 with reproductive effects. Many of the chemicals were found to be strong reproductive toxicants that have yet to be tested in mammals. Chemicals having affect before meiosis I division vs. meiosis II division were identified for 16 gametogenesis-specific chemicals. Finally, we demonstrate that in general yeast reproductive toxicity correlates well with published reproductive toxicity in mammals illustrating the promise of this NAM to quickly assess chemicals to prioritize the evaluation for human reproductive harm.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0890623824000972/pdfft?md5=00345fb20b929dab52ca32fa8795fd8d&pid=1-s2.0-S0890623824000972-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437434","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 : 2024-06-17DOI: 10.1016/j.reprotox.2024.108645
Tat-Chuan Cham , Fahar Ibtisham , Ahmad Al-Dissi , Ali Honaramooz
Male reproductive capacity has fallen considerably in recent decades; in addition, the incidence of testicular cancer has increased in many developed countries. The cause of this phenomenon is unknown, but environmental toxicants are considered a major contributing factor. To study potential reproductive toxicants, robust in vitro testis models are needed. We have recently established a porcine testis organoid system with a high resemblance to the architectures of innate testis tissue. Here, we further investigated the testis morphogenesis, cell maturation, and endocrine function of the testis organoids. We also challenged this system with abiraterone, a steroidogenic inhibitor, to validate its suitability as an in vitro platform for endocrine toxicology tests. Our results showed that the testis cells in the organoids reorganize into testis cordal structures, and the cordal relative areas increase in the organoids over time of culture. Moreover, the diameters and cell numbers per cross-section of the cordal structures increased over time. Interestingly, Sertoli cells in the organoids gradually underwent maturational changes by showing increased expression of androgen receptors, decreased expression of the anti-müllerian hormone, and formation of the blood-testis barrier. Next, we confirmed that the organoids respond to hormonal stimulation and release multiple sex hormones, including testosterone, estradiol, and progesterone. Finally, we showed that the production of testosterone and estradiol in this system can be inhibited in response to the steroidogenic inhibitor. Taken together, our organoid system provides a promising in vitro platform for male reproductive toxicology studies on testis morphogenesis, somatic cell maturation, and endocrine production.
{"title":"An in vitro testicular organoid model for the study of testis morphogenesis, somatic cell maturation, endocrine function, and toxicological assessment of endocrine disruptors","authors":"Tat-Chuan Cham , Fahar Ibtisham , Ahmad Al-Dissi , Ali Honaramooz","doi":"10.1016/j.reprotox.2024.108645","DOIUrl":"https://doi.org/10.1016/j.reprotox.2024.108645","url":null,"abstract":"<div><p>Male reproductive capacity has fallen considerably in recent decades; in addition, the incidence of testicular cancer has increased in many developed countries. The cause of this phenomenon is unknown, but environmental toxicants are considered a major contributing factor. To study potential reproductive toxicants, robust <em>in vitro</em> testis models are needed. We have recently established a porcine testis organoid system with a high resemblance to the architectures of innate testis tissue. Here, we further investigated the testis morphogenesis, cell maturation, and endocrine function of the testis organoids. We also challenged this system with abiraterone, a steroidogenic inhibitor, to validate its suitability as an <em>in vitro</em> platform for endocrine toxicology tests. Our results showed that the testis cells in the organoids reorganize into testis cordal structures, and the cordal relative areas increase in the organoids over time of culture. Moreover, the diameters and cell numbers per cross-section of the cordal structures increased over time. Interestingly, Sertoli cells in the organoids gradually underwent maturational changes by showing increased expression of androgen receptors, decreased expression of the anti-müllerian hormone, and formation of the blood-testis barrier. Next, we confirmed that the organoids respond to hormonal stimulation and release multiple sex hormones, including testosterone, estradiol, and progesterone. Finally, we showed that the production of testosterone and estradiol in this system can be inhibited in response to the steroidogenic inhibitor. Taken together, our organoid system provides a promising <em>in vitro</em> platform for male reproductive toxicology studies on testis morphogenesis, somatic cell maturation, and endocrine production.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0890623824001126/pdfft?md5=d9c0b85b338e25d22d8f54f36844534c&pid=1-s2.0-S0890623824001126-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141422968","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 : 2024-06-14DOI: 10.1016/j.reprotox.2024.108644
Luyao Yang , Shuangshuang Wang , Jing Jin , Jiahui Wang , Wenyue Chen , Yun Xue , Liang Sheng , Yongning Zhai , Weifeng Yao
Sucralose, the extensively utilized sweetener, might lead to metabolic disorders with prolonged consumption, but it remains uncertain if sucralose has any impact on female reproductive health. We incorporated sucralose into drinking water and observed food intake, body weight, estrous cycle, follicular development, serum hormones, and insulin sensitivity of mice. The mice did not experience any changes in their food intake or body weight after consuming sucralose. However, they displayed irregularities in the estrous cycle, marked by a reduced count of primordial, primary, and secondary follicles, coupled with a significant increase in the number of antral follicles. There was a decline in follicle-stimulating hormone (FSH), estradiol (E2), and progesterone (P4) levels, while testosterone (T) and luteinizing hormone (LH) levels surged, leading to a notable elevation in the LH / FSH ratio. Sucralose also induced insulin resistance, as evidenced by elevated insulin levels and impaired insulin tolerance, which responded to an increase in bacterial-derived serum endotoxin. By eliminating insulin resistance with rosiglitazone (RSG), eradicating intestinal flora-derived endotoxins with neomycin (NEO), or enhancing intestinal barrier function with indole-3-carbinol (I3C), the abnormalities in estrous cycle, disruptions in follicular development, hormonal imbalances and elevation in serum endotoxins induced by sucralose were successfully reversed. The present study indicates that sucralose-induced follicular dysplasia in mice is probably related to impaired intestinal permeability, infiltration of endotoxins, initiation of systemic inflammation, and insulin resistance.
{"title":"Sucralose triggers insulin resistance leading to follicular dysplasia in mice","authors":"Luyao Yang , Shuangshuang Wang , Jing Jin , Jiahui Wang , Wenyue Chen , Yun Xue , Liang Sheng , Yongning Zhai , Weifeng Yao","doi":"10.1016/j.reprotox.2024.108644","DOIUrl":"10.1016/j.reprotox.2024.108644","url":null,"abstract":"<div><p>Sucralose, the extensively utilized sweetener, might lead to metabolic disorders with prolonged consumption, but it remains uncertain if sucralose has any impact on female reproductive health. We incorporated sucralose into drinking water and observed food intake, body weight, estrous cycle, follicular development, serum hormones, and insulin sensitivity of mice. The mice did not experience any changes in their food intake or body weight after consuming sucralose. However, they displayed irregularities in the estrous cycle, marked by a reduced count of primordial, primary, and secondary follicles, coupled with a significant increase in the number of antral follicles. There was a decline in follicle-stimulating hormone (FSH), estradiol (E2), and progesterone (P4) levels, while testosterone (T) and luteinizing hormone (LH) levels surged, leading to a notable elevation in the LH / FSH ratio. Sucralose also induced insulin resistance, as evidenced by elevated insulin levels and impaired insulin tolerance, which responded to an increase in bacterial-derived serum endotoxin. By eliminating insulin resistance with rosiglitazone (RSG), eradicating intestinal flora-derived endotoxins with neomycin (NEO), or enhancing intestinal barrier function with indole-3-carbinol (I3C), the abnormalities in estrous cycle, disruptions in follicular development, hormonal imbalances and elevation in serum endotoxins induced by sucralose were successfully reversed. The present study indicates that sucralose-induced follicular dysplasia in mice is probably related to impaired intestinal permeability, infiltration of endotoxins, initiation of systemic inflammation, and insulin resistance.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141331646","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 : 2024-06-14DOI: 10.1016/j.reprotox.2024.108646
Jiawei Sun , Huan Chen , Xu Xu , Yaping Dou , Baofa Wu , Hongyang Zhang , Song Shang , Wuzhuang Sun
Objective
To investigate the impact of maternal smoking on chronic obstructive pulmonary disease (COPD) progression in offspring.
Methods
Using female C57BL/6 J mice, a maternal cigarette smoke exposure (CSE) model was established. Mice were exposed to cigarette smoke for 2 hours/day, 7 days/week, with a minimum 4-hour interval between exposures. Experimental groups included control (Con), pregnancy exposure (AS), pre-pregnancy exposure (SA), and pre-pregnancy + pregnancy exposure (SS). Lung function tests (Penh, PAU, TVb, EF50, Tr) were conducted on male offspring at 7 weeks. Histopathology, electron microscopy, and protein level changes were examined.
Results
Lung function tests revealed significant impairments in Penh, PAU, TVb, EF50, and Tr in offspring across all exposure scenarios. Specifically, AS experienced significant lung function impairment and mitochondrial dysfunction in offspring, with noticeable pulmonary lesions and increased apoptosis. SA showed similar or even more severe lung function impairment and cellular apoptosis. SS exhibited the most pronounced effects, with the highest levels of lung dysfunction, mitochondrial damage, and apoptosis. Histopathological analysis showed pulmonary lesions in offspring exposed to maternal CSE. Flow cytometry revealed increased apoptosis and reduced mitochondrial membrane potential in offspring lung cells. Electron microscopy confirmed mitochondrial dysfunction. Upregulation of apoptotic proteins and downregulation of anti-apoptotic protein Bcl-2 were found in offspring lung tissue exposed to maternal CSE.
Conclusion
Maternal smoking induces impaired lung function, pulmonary lesions, and mitochondrial dysfunction in offspring, regardless of exposure timing and duration. Additionally, it alters expression of apoptosis-related proteins in offspring lung tissue, potentially contributing to COPD susceptibility.
{"title":"Effect of maternal cigarette smoke exposure on COPD progression in offspring mice","authors":"Jiawei Sun , Huan Chen , Xu Xu , Yaping Dou , Baofa Wu , Hongyang Zhang , Song Shang , Wuzhuang Sun","doi":"10.1016/j.reprotox.2024.108646","DOIUrl":"10.1016/j.reprotox.2024.108646","url":null,"abstract":"<div><h3>Objective</h3><p>To investigate the impact of maternal smoking on chronic obstructive pulmonary disease (COPD) progression in offspring.</p></div><div><h3>Methods</h3><p>Using female C57BL/6 J mice, a maternal cigarette smoke exposure (CSE) model was established. Mice were exposed to cigarette smoke for 2 hours/day, 7 days/week, with a minimum 4-hour interval between exposures. Experimental groups included control (Con), pregnancy exposure (AS), pre-pregnancy exposure (SA), and pre-pregnancy + pregnancy exposure (SS). Lung function tests (Penh, PAU, TVb, EF50, Tr) were conducted on male offspring at 7 weeks. Histopathology, electron microscopy, and protein level changes were examined.</p></div><div><h3>Results</h3><p>Lung function tests revealed significant impairments in Penh, PAU, TVb, EF50, and Tr in offspring across all exposure scenarios. Specifically, AS experienced significant lung function impairment and mitochondrial dysfunction in offspring, with noticeable pulmonary lesions and increased apoptosis. SA showed similar or even more severe lung function impairment and cellular apoptosis. SS exhibited the most pronounced effects, with the highest levels of lung dysfunction, mitochondrial damage, and apoptosis. Histopathological analysis showed pulmonary lesions in offspring exposed to maternal CSE. Flow cytometry revealed increased apoptosis and reduced mitochondrial membrane potential in offspring lung cells. Electron microscopy confirmed mitochondrial dysfunction. Upregulation of apoptotic proteins and downregulation of anti-apoptotic protein Bcl-2 were found in offspring lung tissue exposed to maternal CSE.</p></div><div><h3>Conclusion</h3><p>Maternal smoking induces impaired lung function, pulmonary lesions, and mitochondrial dysfunction in offspring, regardless of exposure timing and duration. Additionally, it alters expression of apoptosis-related proteins in offspring lung tissue, potentially contributing to COPD susceptibility.</p></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141331645","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}