Human beings are increasingly exposed to phthalates,which are a group of chemicals used to make plastics more flexible and harder to break,and simultaneously ingesting abundant food emulsifiers via daily diet.The purp...Human beings are increasingly exposed to phthalates,which are a group of chemicals used to make plastics more flexible and harder to break,and simultaneously ingesting abundant food emulsifiers via daily diet.The purpose of this study was to investigate the effect of the food emulsifier glycerin monostearate(GMS)on male reproductive toxicity caused by di(2-ethylhexyl)phthalate(DEHP,one of the phthalates)and explore the underlying mechanism.Thirty male Sprague-Dawley rats were randomly divided into control group,DEHP group and DEHP+GMS group.Rats in the DEHP group and DEHP+GMS group were orally administered with 200 mg/kg/d DEHP with or without 20 mg/kg/d GMS.After 30 days of continuous intervention,it was found that the serum testosterone level was significantly lowered in DEHP group and DEHP+GMS group than that in control group(P<0.01).The serum testosterone level and the relative testis weight were significantly decreased in the DEHP+GMS group as compared with those in the DEHP group and control group(P<0.05).More spermatids were observed to be shed off in DEHP+GMS group than in DEHP group.The expression levels of cell cycle checkpoint kinase 1(Chkl),cell division cycle gene 2(Cdc2),and cyclin-dependent kinase 2(CDK2)were down-regulated in DEHP group,and this tendency was more significant in DEHP+GMS group(P<0.05 or P<0.01).There was no significant difference in the P-glycoprotein(P-gp)expression between DEHP group and control group.However,P-gp was markedly down-regulated in DEHP+GMS group(P<O.Ol).The results indicated that the food emulsifier GMS aggravated the toxicity of DEHP on male reproduction by inhibiting the cell cycle of testicular cells and the expression of P-gp in testis tissues.展开更多
Background: The traditional culture of eating wood-ash extracts in some countries has led to many health problems.The study assessed the anti-fertility effects of the aqueous wood-ash extract of Parkia biglobosa on fe...Background: The traditional culture of eating wood-ash extracts in some countries has led to many health problems.The study assessed the anti-fertility effects of the aqueous wood-ash extract of Parkia biglobosa on female Swissalbino mice. Methods: Healthy female albino mice were procured and randomly grouped into four groups (5/group)where control, 5, 50 and 100 mg/kg doses of the extract were orally administered for 20 days and microscopy ofvaginal smear carried out daily to determine anti-ovulatory activity. Oestrus cycle, including metestrus, diestrus andoestrus phases and histopathology of the uterus were examined daily and at the termination of the experiment.Results: At the end of the study, the highest number of circles (4.80 ± 0.20) was recorded in the control group,administered distilled water, while the lowest number of circles (3.00 ± 0.32) was in the 100 mg/kg dose group.Oestrus (5.80 ± 0.37) also is highest in the control group and lowest (1.20 ± 0.37) in the 100 mg/kg dose group. Thegroup administered 100 mg/kg dose of the aqueous wood-ash extract of Parkia biglobosa had the highest diestrusindex of 45, while the lowest of 17 was obtained in the control group. Histopathology of the uterus tissues shows afew degenerate epithelial cells in 50 mg/kg group and moderate dilatation of lumen and glandular epithelial cells in100 mg/kg group. Conclusion: The study revealed dose-dependent anti-fertility effects of the aqueous wood-ashextract of Parkia biglobosa on female albino mice, which implies its potential reproductive toxicity in humans.展开更多
This work was designed to investigate the acute and reproductive toxicity activity of the aqueous extract of the dry seeds of <i>Aframomum</i> <i>daniellii</i> on the female rats. The acute tox...This work was designed to investigate the acute and reproductive toxicity activity of the aqueous extract of the dry seeds of <i>Aframomum</i> <i>daniellii</i> on the female rats. The acute toxicity of the aqueous extract of <i>Aframomum</i> <i>daniellii</i> (<i>A.</i> <i>daniellii</i>) was evaluated with 6 female rats which were divided into 2 groups (1 Test group and the Control group) of 3 female rats each. The control group received distilled water (10 mL/kg/<i>po</i>) and the test group received a single dose of extract of <i>A.</i> <i>daniellii</i> at the dose of 2000 mg/kg. The reproductive toxicity was evaluated using 45 adult female rats which were divided into 5 groups. Group I, received distilled water (1 mL/100 g/<i>po</i>, neutral control);group II, received Clomiphene citrate (600 μg/kg/<i>po</i>, positive control);Groups III, IV and V (trials) received aqueous extract of <i>A.</i> <i>daniellii</i> at doses of 100, 200 and 400 mg/kg/<i>po</i> respectively. The animals were treated daily for 14 days. From the 6<sup>th</sup> day of treatment, the rats were mated with males of proven fertility for 8 days. On day 22, after laparotomy and delivery, the number of implantation sites, corpora lutea, resorption sites and pups were recorded. Concerning the acute toxicity, it was observed that, after the single dose of 2000 mg/kg administration of the aqueous extract of the dry seeds of <i>A.</i> <i>daniellii</i>, no deaths were recorded. Concerning the reproductive toxicity, no implantation and gestation were observed when compared to the control. However, the aqueous extract of <i>A.</i> <i>daniellii</i> caused a significant (p < 0.001) increase in serum estrogen levels in all treated rats when compared to the control. These results indicate that, the aqueous extract of the dry seeds of <i>A</i> <i>daniellii</i> is weakly toxic, but could negatively affect some reproductive parameters.展开更多
2,6-Dichloro-1,4-benzoquinone(2,6-DCBQ), an emerging water disinfection by-product, is widely detected in water resources. However, its potential effects on the reproductive system are largely unknown. Here, we invest...2,6-Dichloro-1,4-benzoquinone(2,6-DCBQ), an emerging water disinfection by-product, is widely detected in water resources. However, its potential effects on the reproductive system are largely unknown. Here, we investigated the long-term effects of 2,6-DCBQ on gonadal development by exposing zebrafish from 15 to 180 days postfertilization(dpf). Following exposure to 2,6-DCBQ(20 and 100 μg/L), female-specific effects including delayed puberty onset, retarded ovarian growth and breakdown of the zona radiata were observed, resulting in subfertility in adult females. Adverse effects in folliculogenesis disappeared two months after cessation of 2,6-DCBQ administration. In contrast, no adverse impacts were noted in male testes. The effects on females were associated with significant reduction in 17 β-estradiol(E2) level, suggesting a role for 2,6-DCBQ in anti-estrogenic activity. E2 level change in blood was further supported by dysregulated expression of genes( cyp19a1a, fshb, kiss3, esr2b, vtg1, and vtg3) related to the hypothalamic-pituitary-gonad-liver(HPGL) axis. The present study demonstrates for the first time that 2,6-DCBQ induces reproductive impairments in female zebrafish through disrupting 17 β-estradiol level.展开更多
Spermatogenic dysfunction caused by cyclophosphamide(CP)chemotherapy has seriously influenced the life quality of patients.Unfortunately,treatments for CP-induced testicular spermatogenic dysfunction are limited,and t...Spermatogenic dysfunction caused by cyclophosphamide(CP)chemotherapy has seriously influenced the life quality of patients.Unfortunately,treatments for CP-induced testicular spermatogenic dysfunction are limited,and the molecular mechanisms are not fully understood.For the first time,here,we explored the effects of bone marrow mesenchymal stem cell-derived exosomes(BMSC-exos)on CP-induced testicular spermatogenic dysfunction in vitro and in vivo.BMSC-exos could be taken up by spermatogonia(GC1-spg cells).CP-injured GC1-spg cells and BMSC-exos were cocultured at various doses,and then,cell proliferation was measured using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)assay.In addition,photophosphorylation of extracellular-regulated kinase(ERK),p38 mitogen-activated protein kinase(p38MAPK),and protein kinase B(AKT)proteins was evaluated by western blotting as well as apoptosis in GC1-spg cells measured using flow cytometry.Treatment with BMSC-exos enhanced cell proliferation and reduced apoptosis of CP-injured GCI-spg cells.Phosphorylated levels of ERK,AKT,and p38MAPK proteins were reduced in CP-injured spermatogonia when co-treated with BMSC-exos,indicating that BMSC-exos acted against the reproductive toxicity of CP via the p38MAPK/ERK and AKT signaling pathways.In experiments in vivo,CP-treated rats received BMSC-exos by injection into the tail vein,and testis morphology was compared between treated and control groups.Histology showed that transfusion of BMSC-exos inhibited the pathological changes in CP-injured testes.Thus,BMSC-exos could counteract the reproductive toxicity of CP via the p38MAPK/ERK and AKT signaling pathways.The findings provide a potential treatment for CP-induced male spermatogenic dysfunction using BMSC-exos.展开更多
Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treatin...Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treating inflammatory-related diseases,its well-known safety issues,especially reproductive toxicity has aroused concerns.However,a comprehensive dissection of triptolide-associated testicular toxicity at single cell resolution is still lacking.Here,we observed testicular toxicity after 14 days of triptolide exposure,and then constructed a single-cell transcriptome map of 59,127 cells in mouse testes upon triptolide-treatment.We identified triptolide-associated shared and cell-type specific differentially expressed genes,enriched pathways,and ligand-receptor pairs in different cell types of mouse testes.In addition to the loss of germ cells,our results revealed increased macrophages and the inflammatory response in triptolide-treated mouse testes,suggesting a critical role of inflammation in triptolide-induced testicular injury.We also found increased reactive oxygen species(ROS)signaling and downregulated pathways associated with spermatid development in somatic cells,especially Leydig and Sertoli cells,in triptolide-treated mice,indicating that dysregulation of these signaling pathways may contribute to triptolide-induced testicular toxicity.Overall,our high-resolution single-cell landscape offers comprehensive information regarding triptolide-associated gene expression profiles in major cell types of mouse testes at single cell resolution,providing an invaluable resource for understanding the underlying mechanism of triptolide-associated testicular injury and additional discoveries of therapeutic targets of triptolide-induced male reproductive toxicity.展开更多
The total fertility rate of women in childbearing age showed a downward trend in China.In addition to the age and genetic factors,environmental endocrine disruption can also impair fertility.The impact of increasing n...The total fertility rate of women in childbearing age showed a downward trend in China.In addition to the age and genetic factors,environmental endocrine disruption can also impair fertility.The impact of increasing new environmental pollutants on the couples in childbearing age has become a research hotspot recently.Phthalate acid esters(PAEs)is a common plasticizer in plastic products,which is widely found in toys,food packaging,construction materials,electronic and medical components,personal care products,office and school supplies and other plastic packaging products,and is the main substance of environmental pollution.Multiple studies have shown that PAEs can not only cause environmental and water pollution,but also have a variety of toxic effects such as reproductive toxicity,genotoxicity,immunotoxicity,neurotoxicity,teratogenicity,and carcinogenesis.Therefore,its impact on human health,especially on reproductive health of people of reproductive age and their offspring,cannot be ignored.However,the current epidemiological study of PAEs and new alternatives in reproductive health population is still controversial,and the toxicity mechanism is still in the exploration stage.This article through to PAEs of parental generation,children(including embryo)of reproductive development and the influence of genetic toxicity research progress at home and abroad to do a review,aims to promote effective control measures for the establishment of PAEs pollutants rather than on reproductive health risk prediction,thus for PAEs of adverse reproductive outcomes of reproductive stage of people provide a scientific basis for precision control and guidance.展开更多
Microplastics(MPs)and nanoplastics(NPs)have become hazardous materials due to the massive amount of plastic waste and disposable masks,but their specific health effects remain uncertain.In this study,fluorescence-labe...Microplastics(MPs)and nanoplastics(NPs)have become hazardous materials due to the massive amount of plastic waste and disposable masks,but their specific health effects remain uncertain.In this study,fluorescence-labeled polystyrene NPs(PS-NPs)were injected into the circulatory systems of mice to determine the distribution and potential toxic effects of NPs in vivo.Interestingly,whole-body imaging found that PS-NPs accumulated in the testes of mice.Therefore,the toxic effects of PS-NPs on the reproduction systems and the spermatocytes cell line of male mice,and their mechanisms,were investigated.After oral exposure to PS-NPs,their spermatogenesis was affected and the spermatogenic cells were damaged.The spermatocyte cell line GC-2 was exposed to PS-NPs and analyzed using RNA sequencing(RNA-seq)to determine the toxic mechanisms;a ferroptosis pathway was found after PS-NP exposure.The phenomena and indicators of ferroptosis were then determined and verified by ferroptosis inhibitor ferrostatin-1(Fer-1),and it was also found that nuclear factor erythroid 2-related factor 2(Nrf2)played an important role in spermatogenic cell ferroptosis induced by PS-NPs.Finally,it was confirmed in vivo that this mechanism of Nrf2 played a protective role in PS-NPs-induced male reproductive toxicity.This study demonstrated that PS-NPs induce male reproductive dysfunction in mice by causing spermatogenic cell ferroptosis dependent on Nrf2.展开更多
Female infertility after occupational exposure to inhaled anesthetic agents has attracted critical attention,but systematic studies focusing on the impact of inhaled anesthetics on the female reproductive system have ...Female infertility after occupational exposure to inhaled anesthetic agents has attracted critical attention,but systematic studies focusing on the impact of inhaled anesthetics on the female reproductive system have not been well-established.We used a murine model to study the effect of isoflurane exposure on infertility in female adult mice and investigated the potential underlying mechanism.One hundred adult female C57 mice were randomly allocated into 5 groups exposed in air containing 0,2500,5000,10000 or 20000 ppm isoflurane for 15 consecutive days.Estrous cycle length was measured based on vaginal smear examination,ovarian histopathologic enumeration of follicles,and serum estradiol(E2),anti-Mullerian hormone(AMH),follicle-stimulating hormone(FSH),and luteinizing hormone(LH)levels to assess the effect of isoflurane on ovarian reserve.Compared to the control group,significant prolongation of the estrous cycle of the adult female mice was observed in the 20000 ppm isoflurane exposure group.Serum AMH was significantly decreased,and FSH and LH levels profoundly increased in the 5000,10000,and 20000 ppm isoflurane exposure groups compared to the control group.The histopathologic examination revealed a reduced number of developing follicles and an increased number of atretic follicles after isoflurane exposure,but the difference was not statistically significant.Thus,exposure to a higher concentration of isoflurane might have an adverse effect on ovarian reserve in sexually-mature female mice.展开更多
Objectives:This study aimed to investigate the effect of the widely used food emulsifier glycerin monostearate(GM)on testicular toxicity caused by the mixture of three commonly used phthalate esters(MPEs)in rats,and f...Objectives:This study aimed to investigate the effect of the widely used food emulsifier glycerin monostearate(GM)on testicular toxicity caused by the mixture of three commonly used phthalate esters(MPEs)in rats,and further to explore the underlying mechanism.Materials and Methods:Thirty male Sprague-Dawley rats were randomly divided into three groups.Rats were orally treated with 160 mg/kg/d MPEs in the MPEs group;coinstantaneously treated with 160 mg/kg/d MPEs and 200 mg/kg/d GM in the MPEs+GM group;and treated with the excipient in the control group.The intervention lasted for 5 weeks.Testis weight,epididymis weight,testicular histopathology,and serum testosterone were detected for testicular toxicity evaluation.The testicular ultrastructure,the tight junction proteins zonula occluden(ZO)-1,and claudin were measured for the mechanism exploration.Results:The body weight,epididymis,serum testosterone level,and anogenital distance in the MPEs+GM group were significantly decreased compared with control group(P<0.05);Testicular histopathological observation showed that shed spermatids were observed in the MPEs+GM group.Ultrastructural observation of testicular cells showed that the cristae number was decreased in some mitochondria in the MPEs group,whereas the cristae were fused and disappeared in most mitochondria in the MPEs+GM group.The tight junctions were broken in the MPEs+GM group;meanwhile,the expression of ZO-1 and claudin were altered in the MPEs+GM group(P<0.01).Conclusions:The results from this study indicated that GM aggravated MPEs'testicular toxicity,which might relate to the injured mitochondria and damaged tight junctions in testicular tissue.展开更多
Background:The growing male reproductive diseases have been linked to higher exposure to certain environmental compounds such as 2,2,4,4-tetrabromodiphenyl ether(BDE47)that are widely distributed in the food chain.How...Background:The growing male reproductive diseases have been linked to higher exposure to certain environmental compounds such as 2,2,4,4-tetrabromodiphenyl ether(BDE47)that are widely distributed in the food chain.However,the specific underlying molecular mechanisms for BDE47-induced male reproductive toxicity are not completely understood.Methods:Here,for the first time,advanced single-cell RNA sequencing(ScRNA-seq)was employed to dissect BDE47-induced prepubertal testicular toxicity in mice from a pool of 76859 cells.Results:Our ScRNA-seq results revealed shared and heterogeneous information of differentially expressed genes,signaling pathways,transcription factors,and ligands-receptors in major testicular cell types in mice upon BDE47 treatment.Apart from disruption of hormone homeostasis,BDE47 was discovered to downregulate multiple previously unappreciated pathways such as double-strand break repair and cytokinesis pathways,indicative of their potential roles involved in BDE47-induced testicular injury.Interestingly,transcription factors analysis of ScRNA-seq results revealed that Kdm5b(lysine-specific demethylase 5B),a key transcription factor required for spermatogenesis,was downregulated in all germ cells as well as in Sertoli and telocyte cells in BDE47-treated testes of mice,suggesting its contribution to BDE47-induced impairment of spermatogenesis.Conclusions:Overall,for the first time,we established the molecular cell atlas of mice testes to define BDE47-induced prepubertal testicular toxicity using the ScRNA-seq approach,providing novel insight into our understanding of the underlying mechanisms and pathways involved in BDE47-associated testicular injury at a single-cell resolution.Our results can serve as an important resource to further dissect the potential roles of BDE47,and other relevant endocrine-disrupting chemicals,in inducing male reproductive toxicity.展开更多
Tetrabromobisphenol A-bis(2,3-dibromopropyl ether)(TBBPA-BDBPE),a widely used flame retardant,has been frequently detected in various environmental compartments,but its health hazard remains largely unknown.Here,we in...Tetrabromobisphenol A-bis(2,3-dibromopropyl ether)(TBBPA-BDBPE),a widely used flame retardant,has been frequently detected in various environmental compartments,but its health hazard remains largely unknown.Here,we investigated the adverse effects of TBBPA-BDBPE(50 and 1000μg/kg/day)on postnatal testis development in CD-1 mice and the underlying mechanism.Following the first week of maternal exposure,neonatal mice in the high-dose group exhibited reduced seminiferous tubule area,fewer Sertoli cells and germ cells,and damaged microtubules in Sertoli cells;even microtubule damage was also observed in the low-dose group.When exposure extended to adulthood,male offspring in the high-dose group presented more remarkable alterations in reproductive parameters,including reduced sperm count;in the low-dose group,microtubule damage was also observable,along with blood−testis barrier impairment.Further molecular docking analysis and tubulin polymerization assay indicated that TBBPA-BDBPE could interact with tubulin and disrupt its polymerization.Moreover,we observed attenuated microtubules in mouse Sertoli cells in vitro(TM4)following TBBPABDBPE treatment,suggesting that TBBPA-BDBPE impaired testis development possibly by interfering with tubulin dynamics.This study not only highlights the male reproductive hazard of TBBPA-BDBPE but also greatly improved the understanding of the molecular mechanism for male reproductive toxicity of chemicals.展开更多
文摘Human beings are increasingly exposed to phthalates,which are a group of chemicals used to make plastics more flexible and harder to break,and simultaneously ingesting abundant food emulsifiers via daily diet.The purpose of this study was to investigate the effect of the food emulsifier glycerin monostearate(GMS)on male reproductive toxicity caused by di(2-ethylhexyl)phthalate(DEHP,one of the phthalates)and explore the underlying mechanism.Thirty male Sprague-Dawley rats were randomly divided into control group,DEHP group and DEHP+GMS group.Rats in the DEHP group and DEHP+GMS group were orally administered with 200 mg/kg/d DEHP with or without 20 mg/kg/d GMS.After 30 days of continuous intervention,it was found that the serum testosterone level was significantly lowered in DEHP group and DEHP+GMS group than that in control group(P<0.01).The serum testosterone level and the relative testis weight were significantly decreased in the DEHP+GMS group as compared with those in the DEHP group and control group(P<0.05).More spermatids were observed to be shed off in DEHP+GMS group than in DEHP group.The expression levels of cell cycle checkpoint kinase 1(Chkl),cell division cycle gene 2(Cdc2),and cyclin-dependent kinase 2(CDK2)were down-regulated in DEHP group,and this tendency was more significant in DEHP+GMS group(P<0.05 or P<0.01).There was no significant difference in the P-glycoprotein(P-gp)expression between DEHP group and control group.However,P-gp was markedly down-regulated in DEHP+GMS group(P<O.Ol).The results indicated that the food emulsifier GMS aggravated the toxicity of DEHP on male reproduction by inhibiting the cell cycle of testicular cells and the expression of P-gp in testis tissues.
文摘Background: The traditional culture of eating wood-ash extracts in some countries has led to many health problems.The study assessed the anti-fertility effects of the aqueous wood-ash extract of Parkia biglobosa on female Swissalbino mice. Methods: Healthy female albino mice were procured and randomly grouped into four groups (5/group)where control, 5, 50 and 100 mg/kg doses of the extract were orally administered for 20 days and microscopy ofvaginal smear carried out daily to determine anti-ovulatory activity. Oestrus cycle, including metestrus, diestrus andoestrus phases and histopathology of the uterus were examined daily and at the termination of the experiment.Results: At the end of the study, the highest number of circles (4.80 ± 0.20) was recorded in the control group,administered distilled water, while the lowest number of circles (3.00 ± 0.32) was in the 100 mg/kg dose group.Oestrus (5.80 ± 0.37) also is highest in the control group and lowest (1.20 ± 0.37) in the 100 mg/kg dose group. Thegroup administered 100 mg/kg dose of the aqueous wood-ash extract of Parkia biglobosa had the highest diestrusindex of 45, while the lowest of 17 was obtained in the control group. Histopathology of the uterus tissues shows afew degenerate epithelial cells in 50 mg/kg group and moderate dilatation of lumen and glandular epithelial cells in100 mg/kg group. Conclusion: The study revealed dose-dependent anti-fertility effects of the aqueous wood-ashextract of Parkia biglobosa on female albino mice, which implies its potential reproductive toxicity in humans.
文摘This work was designed to investigate the acute and reproductive toxicity activity of the aqueous extract of the dry seeds of <i>Aframomum</i> <i>daniellii</i> on the female rats. The acute toxicity of the aqueous extract of <i>Aframomum</i> <i>daniellii</i> (<i>A.</i> <i>daniellii</i>) was evaluated with 6 female rats which were divided into 2 groups (1 Test group and the Control group) of 3 female rats each. The control group received distilled water (10 mL/kg/<i>po</i>) and the test group received a single dose of extract of <i>A.</i> <i>daniellii</i> at the dose of 2000 mg/kg. The reproductive toxicity was evaluated using 45 adult female rats which were divided into 5 groups. Group I, received distilled water (1 mL/100 g/<i>po</i>, neutral control);group II, received Clomiphene citrate (600 μg/kg/<i>po</i>, positive control);Groups III, IV and V (trials) received aqueous extract of <i>A.</i> <i>daniellii</i> at doses of 100, 200 and 400 mg/kg/<i>po</i> respectively. The animals were treated daily for 14 days. From the 6<sup>th</sup> day of treatment, the rats were mated with males of proven fertility for 8 days. On day 22, after laparotomy and delivery, the number of implantation sites, corpora lutea, resorption sites and pups were recorded. Concerning the acute toxicity, it was observed that, after the single dose of 2000 mg/kg administration of the aqueous extract of the dry seeds of <i>A.</i> <i>daniellii</i>, no deaths were recorded. Concerning the reproductive toxicity, no implantation and gestation were observed when compared to the control. However, the aqueous extract of <i>A.</i> <i>daniellii</i> caused a significant (p < 0.001) increase in serum estrogen levels in all treated rats when compared to the control. These results indicate that, the aqueous extract of the dry seeds of <i>A</i> <i>daniellii</i> is weakly toxic, but could negatively affect some reproductive parameters.
基金supported by Xuzhou Medical University start-up grant for excellent scientists (Nos. RC20552044, RC20552054)the Natural Science Research of the Jiangsu Higher Education Institutions (Nos. 21KJB330007, 21KJB320001)。
文摘2,6-Dichloro-1,4-benzoquinone(2,6-DCBQ), an emerging water disinfection by-product, is widely detected in water resources. However, its potential effects on the reproductive system are largely unknown. Here, we investigated the long-term effects of 2,6-DCBQ on gonadal development by exposing zebrafish from 15 to 180 days postfertilization(dpf). Following exposure to 2,6-DCBQ(20 and 100 μg/L), female-specific effects including delayed puberty onset, retarded ovarian growth and breakdown of the zona radiata were observed, resulting in subfertility in adult females. Adverse effects in folliculogenesis disappeared two months after cessation of 2,6-DCBQ administration. In contrast, no adverse impacts were noted in male testes. The effects on females were associated with significant reduction in 17 β-estradiol(E2) level, suggesting a role for 2,6-DCBQ in anti-estrogenic activity. E2 level change in blood was further supported by dysregulated expression of genes( cyp19a1a, fshb, kiss3, esr2b, vtg1, and vtg3) related to the hypothalamic-pituitary-gonad-liver(HPGL) axis. The present study demonstrates for the first time that 2,6-DCBQ induces reproductive impairments in female zebrafish through disrupting 17 β-estradiol level.
基金This study was supported by grants from the National Natural Science Foundation of China(No.81772257)the Guangdong Provincial Natural Science Foundation of China(No.2018A030313697).
文摘Spermatogenic dysfunction caused by cyclophosphamide(CP)chemotherapy has seriously influenced the life quality of patients.Unfortunately,treatments for CP-induced testicular spermatogenic dysfunction are limited,and the molecular mechanisms are not fully understood.For the first time,here,we explored the effects of bone marrow mesenchymal stem cell-derived exosomes(BMSC-exos)on CP-induced testicular spermatogenic dysfunction in vitro and in vivo.BMSC-exos could be taken up by spermatogonia(GC1-spg cells).CP-injured GC1-spg cells and BMSC-exos were cocultured at various doses,and then,cell proliferation was measured using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)assay.In addition,photophosphorylation of extracellular-regulated kinase(ERK),p38 mitogen-activated protein kinase(p38MAPK),and protein kinase B(AKT)proteins was evaluated by western blotting as well as apoptosis in GC1-spg cells measured using flow cytometry.Treatment with BMSC-exos enhanced cell proliferation and reduced apoptosis of CP-injured GCI-spg cells.Phosphorylated levels of ERK,AKT,and p38MAPK proteins were reduced in CP-injured spermatogonia when co-treated with BMSC-exos,indicating that BMSC-exos acted against the reproductive toxicity of CP via the p38MAPK/ERK and AKT signaling pathways.In experiments in vivo,CP-treated rats received BMSC-exos by injection into the tail vein,and testis morphology was compared between treated and control groups.Histology showed that transfusion of BMSC-exos inhibited the pathological changes in CP-injured testes.Thus,BMSC-exos could counteract the reproductive toxicity of CP via the p38MAPK/ERK and AKT signaling pathways.The findings provide a potential treatment for CP-induced male spermatogenic dysfunction using BMSC-exos.
基金supported by grants from the National Key Research and Development Program of China(Grant Nos.:2020YFA0908000,2022YFC2303600)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.:ZYYCXTD-C-202002)+7 种基金the National Natural Science Foundation of China(Grant Nos.:82201786,82141001,82274182,82074098,82173914)the CACMS Innovation Fund(Grant Nos.:CI2021A05101,CI2021A05104)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(Grant No.:CI2021B014)the Science and Technology Foundation of Shenzhen(Grant Nos.:JCYJ20220818102613029,JCYJ20210324114014039,JCYJ20210324115800001)Guangdong Basic and Applied Basic Research Foundation(Grant Nos.:2020A1515110549,2021A1515110646)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)the National Key R&D Program of China Key projects for international cooperation on science,technology and innovation(Grant No.:2020YFE0205100)and the Fundamental Research Funds for the Central Public Welfare Research Institutes(Grant Nos.:ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-FL-002,ZZ14-ND-010,ZZ15-ND-10).
文摘Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treating inflammatory-related diseases,its well-known safety issues,especially reproductive toxicity has aroused concerns.However,a comprehensive dissection of triptolide-associated testicular toxicity at single cell resolution is still lacking.Here,we observed testicular toxicity after 14 days of triptolide exposure,and then constructed a single-cell transcriptome map of 59,127 cells in mouse testes upon triptolide-treatment.We identified triptolide-associated shared and cell-type specific differentially expressed genes,enriched pathways,and ligand-receptor pairs in different cell types of mouse testes.In addition to the loss of germ cells,our results revealed increased macrophages and the inflammatory response in triptolide-treated mouse testes,suggesting a critical role of inflammation in triptolide-induced testicular injury.We also found increased reactive oxygen species(ROS)signaling and downregulated pathways associated with spermatid development in somatic cells,especially Leydig and Sertoli cells,in triptolide-treated mice,indicating that dysregulation of these signaling pathways may contribute to triptolide-induced testicular toxicity.Overall,our high-resolution single-cell landscape offers comprehensive information regarding triptolide-associated gene expression profiles in major cell types of mouse testes at single cell resolution,providing an invaluable resource for understanding the underlying mechanism of triptolide-associated testicular injury and additional discoveries of therapeutic targets of triptolide-induced male reproductive toxicity.
基金Hainan Province Clinical Medical Center (No.QWYH202175).
文摘The total fertility rate of women in childbearing age showed a downward trend in China.In addition to the age and genetic factors,environmental endocrine disruption can also impair fertility.The impact of increasing new environmental pollutants on the couples in childbearing age has become a research hotspot recently.Phthalate acid esters(PAEs)is a common plasticizer in plastic products,which is widely found in toys,food packaging,construction materials,electronic and medical components,personal care products,office and school supplies and other plastic packaging products,and is the main substance of environmental pollution.Multiple studies have shown that PAEs can not only cause environmental and water pollution,but also have a variety of toxic effects such as reproductive toxicity,genotoxicity,immunotoxicity,neurotoxicity,teratogenicity,and carcinogenesis.Therefore,its impact on human health,especially on reproductive health of people of reproductive age and their offspring,cannot be ignored.However,the current epidemiological study of PAEs and new alternatives in reproductive health population is still controversial,and the toxicity mechanism is still in the exploration stage.This article through to PAEs of parental generation,children(including embryo)of reproductive development and the influence of genetic toxicity research progress at home and abroad to do a review,aims to promote effective control measures for the establishment of PAEs pollutants rather than on reproductive health risk prediction,thus for PAEs of adverse reproductive outcomes of reproductive stage of people provide a scientific basis for precision control and guidance.
基金supported by the National Natural Science Foundation of China(No.82204094)the Key Research and Development Program of Ningxia(No.2022BEG03084)the National Key Research and Development Program of China(No.2018YFC1004202)。
文摘Microplastics(MPs)and nanoplastics(NPs)have become hazardous materials due to the massive amount of plastic waste and disposable masks,but their specific health effects remain uncertain.In this study,fluorescence-labeled polystyrene NPs(PS-NPs)were injected into the circulatory systems of mice to determine the distribution and potential toxic effects of NPs in vivo.Interestingly,whole-body imaging found that PS-NPs accumulated in the testes of mice.Therefore,the toxic effects of PS-NPs on the reproduction systems and the spermatocytes cell line of male mice,and their mechanisms,were investigated.After oral exposure to PS-NPs,their spermatogenesis was affected and the spermatogenic cells were damaged.The spermatocyte cell line GC-2 was exposed to PS-NPs and analyzed using RNA sequencing(RNA-seq)to determine the toxic mechanisms;a ferroptosis pathway was found after PS-NP exposure.The phenomena and indicators of ferroptosis were then determined and verified by ferroptosis inhibitor ferrostatin-1(Fer-1),and it was also found that nuclear factor erythroid 2-related factor 2(Nrf2)played an important role in spermatogenic cell ferroptosis induced by PS-NPs.Finally,it was confirmed in vivo that this mechanism of Nrf2 played a protective role in PS-NPs-induced male reproductive toxicity.This study demonstrated that PS-NPs induce male reproductive dysfunction in mice by causing spermatogenic cell ferroptosis dependent on Nrf2.
基金This work was supported by the National Key Research and Development Program(No.2018YFC1002103).
文摘Female infertility after occupational exposure to inhaled anesthetic agents has attracted critical attention,but systematic studies focusing on the impact of inhaled anesthetics on the female reproductive system have not been well-established.We used a murine model to study the effect of isoflurane exposure on infertility in female adult mice and investigated the potential underlying mechanism.One hundred adult female C57 mice were randomly allocated into 5 groups exposed in air containing 0,2500,5000,10000 or 20000 ppm isoflurane for 15 consecutive days.Estrous cycle length was measured based on vaginal smear examination,ovarian histopathologic enumeration of follicles,and serum estradiol(E2),anti-Mullerian hormone(AMH),follicle-stimulating hormone(FSH),and luteinizing hormone(LH)levels to assess the effect of isoflurane on ovarian reserve.Compared to the control group,significant prolongation of the estrous cycle of the adult female mice was observed in the 20000 ppm isoflurane exposure group.Serum AMH was significantly decreased,and FSH and LH levels profoundly increased in the 5000,10000,and 20000 ppm isoflurane exposure groups compared to the control group.The histopathologic examination revealed a reduced number of developing follicles and an increased number of atretic follicles after isoflurane exposure,but the difference was not statistically significant.Thus,exposure to a higher concentration of isoflurane might have an adverse effect on ovarian reserve in sexually-mature female mice.
基金the National Natural Science Foundation of China(No.81903321)the Wenzhou Municipal Science and Technology Bureau(Y2020098),ChinaResearch and the Development Fund Project of Wenzhou Medical University(QTJ17019,QTJ18001),China.
文摘Objectives:This study aimed to investigate the effect of the widely used food emulsifier glycerin monostearate(GM)on testicular toxicity caused by the mixture of three commonly used phthalate esters(MPEs)in rats,and further to explore the underlying mechanism.Materials and Methods:Thirty male Sprague-Dawley rats were randomly divided into three groups.Rats were orally treated with 160 mg/kg/d MPEs in the MPEs group;coinstantaneously treated with 160 mg/kg/d MPEs and 200 mg/kg/d GM in the MPEs+GM group;and treated with the excipient in the control group.The intervention lasted for 5 weeks.Testis weight,epididymis weight,testicular histopathology,and serum testosterone were detected for testicular toxicity evaluation.The testicular ultrastructure,the tight junction proteins zonula occluden(ZO)-1,and claudin were measured for the mechanism exploration.Results:The body weight,epididymis,serum testosterone level,and anogenital distance in the MPEs+GM group were significantly decreased compared with control group(P<0.05);Testicular histopathological observation showed that shed spermatids were observed in the MPEs+GM group.Ultrastructural observation of testicular cells showed that the cristae number was decreased in some mitochondria in the MPEs group,whereas the cristae were fused and disappeared in most mitochondria in the MPEs+GM group.The tight junctions were broken in the MPEs+GM group;meanwhile,the expression of ZO-1 and claudin were altered in the MPEs+GM group(P<0.01).Conclusions:The results from this study indicated that GM aggravated MPEs'testicular toxicity,which might relate to the injured mitochondria and damaged tight junctions in testicular tissue.
基金supported by the National Natural Science Foundation of China(Grant No.82003721)Shenzhen Science and Technology Innovation Commission(Grants No.JCYJ20210324114014039 and JCYJ20210324115800001)+4 种基金China Postdoctoral Science Foundation(Grant No.2020M683182)Guangdong Basic and Applied Basic Research Foundation(Grant No.2020A1515110549)the National Key Research and Development Program of China(Grant No.2020YFA0908000)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.ZYYCXTD-C-202002)the Sanming Project of Medicine in Shenzhen(Grant No.SZSM201612034).
文摘Background:The growing male reproductive diseases have been linked to higher exposure to certain environmental compounds such as 2,2,4,4-tetrabromodiphenyl ether(BDE47)that are widely distributed in the food chain.However,the specific underlying molecular mechanisms for BDE47-induced male reproductive toxicity are not completely understood.Methods:Here,for the first time,advanced single-cell RNA sequencing(ScRNA-seq)was employed to dissect BDE47-induced prepubertal testicular toxicity in mice from a pool of 76859 cells.Results:Our ScRNA-seq results revealed shared and heterogeneous information of differentially expressed genes,signaling pathways,transcription factors,and ligands-receptors in major testicular cell types in mice upon BDE47 treatment.Apart from disruption of hormone homeostasis,BDE47 was discovered to downregulate multiple previously unappreciated pathways such as double-strand break repair and cytokinesis pathways,indicative of their potential roles involved in BDE47-induced testicular injury.Interestingly,transcription factors analysis of ScRNA-seq results revealed that Kdm5b(lysine-specific demethylase 5B),a key transcription factor required for spermatogenesis,was downregulated in all germ cells as well as in Sertoli and telocyte cells in BDE47-treated testes of mice,suggesting its contribution to BDE47-induced impairment of spermatogenesis.Conclusions:Overall,for the first time,we established the molecular cell atlas of mice testes to define BDE47-induced prepubertal testicular toxicity using the ScRNA-seq approach,providing novel insight into our understanding of the underlying mechanisms and pathways involved in BDE47-associated testicular injury at a single-cell resolution.Our results can serve as an important resource to further dissect the potential roles of BDE47,and other relevant endocrine-disrupting chemicals,in inducing male reproductive toxicity.
基金supported by the National Key Research and Development Program of China(2018YFA0901103)the National Natural Science Foundation of China(21876196).
文摘Tetrabromobisphenol A-bis(2,3-dibromopropyl ether)(TBBPA-BDBPE),a widely used flame retardant,has been frequently detected in various environmental compartments,but its health hazard remains largely unknown.Here,we investigated the adverse effects of TBBPA-BDBPE(50 and 1000μg/kg/day)on postnatal testis development in CD-1 mice and the underlying mechanism.Following the first week of maternal exposure,neonatal mice in the high-dose group exhibited reduced seminiferous tubule area,fewer Sertoli cells and germ cells,and damaged microtubules in Sertoli cells;even microtubule damage was also observed in the low-dose group.When exposure extended to adulthood,male offspring in the high-dose group presented more remarkable alterations in reproductive parameters,including reduced sperm count;in the low-dose group,microtubule damage was also observable,along with blood−testis barrier impairment.Further molecular docking analysis and tubulin polymerization assay indicated that TBBPA-BDBPE could interact with tubulin and disrupt its polymerization.Moreover,we observed attenuated microtubules in mouse Sertoli cells in vitro(TM4)following TBBPABDBPE treatment,suggesting that TBBPA-BDBPE impaired testis development possibly by interfering with tubulin dynamics.This study not only highlights the male reproductive hazard of TBBPA-BDBPE but also greatly improved the understanding of the molecular mechanism for male reproductive toxicity of chemicals.
