Germ Cell Apoptosis Research Articles

Contamination Characterization, Toxicological Properties, and Health Risk Assessment of Bisphenols in Multiple Media: Current Research Status and Future Perspectives

Bisphenols (BPs) are ubiquitous environmental endocrine disruptors that cause various human health hazards and pollute water, soil, and the atmosphere to varying degrees. Although various studies have investigated the pollution characteristics and health hazards of BPs in different media, a systematic review of BPs in the broader environmental context is still lacking. This study highlights the pollution characteristics, detection methods, and risk assessment status of BPs by combining relevant studies from both domestic and international sources, and their environmental distribution characteristics are summarized. The results show that BP pollution is a widespread and complex global phenomenon. Bisphenol A (BPA) remains the predominant component of BPs, which can damage the nervous and reproductive systems. At present, high-performance liquid chromatography–tandem mass spectrometry, high-performance liquid chromatography, and liquid chromatography–tandem mass spectrometry are the main detection methods used for BPs. BPs can also damage the reproductive system, leading to germ cell apoptosis and ovarian damage. Future research should focus on expanding the BP testing repertoire, advancing rapid detection techniques, elucidating toxic mechanisms, conducting comprehensive safety assessments, and developing systematic health risk assessment methods. These efforts will provide a scientific foundation for preventing and controlling emerging pollutants.

Research Progress on Reproductive Toxicity and Reversibility of Tripterygium wilfordii Based on Gender Differences

Tripterygium wilfordii Hook F. (TwHF), a member of the Celastraceae family and belonging to the genus Tripterygium, is a vine-like shrub. It contains numerous active components, such as Tripterygium glycosides (GTW) and triptolide (TP), widely known for their significant reproductive toxicity. This toxicity is characterized by its detrimental effects on the testes and ovaries, leading to reduced libido, apoptosis of germ and follicle cells, and abnormal secretion of sex hormones. Thus, it is necessary to explore the mechanisms behind TwHF’s reproductive toxicity, which will lead to advancements in detoxification and efficacy enhancement strategies. This article offers a comprehensive overview and analysis of the research conducted on reproductive toxicity and its reversibility induced by TwHF, aiming to provide a reference for its rational use in clinical settings.

Combined Effects of Chrysin Supplementation and Exercise Training on Diabetes-Induced Oxidative Stress and Apoptosis in Rat Testicular Tissue.

Diabetes mellitus (DM), one of the most pervasive and enduring metabolic diseases, has been demonstrated to adversely impact male fertility. Conversely, both exercise training and Chrysin have been identified as potential interventions capable of mitigating the deleterious effects of diabetes on spermatogenesis. Thus, the current study aims to explore the individual and combined influences of Chrysin supplementation and running exercise on oxidative stress and germ cell apoptosis in the testicular tissue of diabetic adult rats. In this experimental study, the DM was induced by streptozotocin (STZ,50 mg/kg). Rats were divided into control (received STZ solvent), DM-sole, Chrysin-sole (50 mg/kg, daily), moderate-intensity running exercise training (MIRET-sole, warm-up, 5 minutes at 30% of Smax1 (Maximum speed); Moderate intensity exercise, 60 minutes at 60% of Smax1, and recovery, 5 minutes to 30% of Smax1), DM+Chrysin, DM+MIRET, and DM+MIRET+Chrysin. Following 8 weeks, the histopathological changes (Johnson's score, epithelial height, and tubular diameter), testicular malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX), and the mRNA levels of anti-apoptotic gene Bcl-2 and pro-apoptotic gene Bax was analyzed. Chrysin solely and simultaneous with MIRET could remarkably (P=0.001) improve the DM-induced histopathological damages, increase the testicular SOD and GPx levels, and decline the DM-increased MDA content. Moreover, our results showed that Chrysin solely and more simultaneously with MIRET could significantly (P=0.001) decrease the mRNA expression of Bax and improve the Bcl-2 expression and rebalance the Bax/Bcl-2 balance. Our findings showed that co-administration of Chrysin along with MIRET can significantly ameliorate the DM-induced histopathological, and biochemical impairments and reduce the pro-apoptotic impact of DM on testicular tissue.

Acupuncture Increased the Number of Retrieved Oocytes in a Mouse Model of POR: The Involvement of DNA Methylation in the Oocytes

Background: Poor ovarian response (POR) reduces the success rate of in vitro fertilization mainly because of fewer oocytes retrieved. Acupuncture (Ac) therapy can improve the number of retrieved oocytes in the controlled ovarian stimulation program. The role of Ac in the corresponding epigenetic mechanism of POR has not been studied. Objective: This study was conducted to determine the effect of Ac on the number of retrieved oocytes and its role in DNA methylation in a mouse model of POR. Methods:: Forty C57BL/6N female mice with normal estrous cycles were randomly classified into 4 groups of 10 each: control (Con) group, Ac-Con group, POR group, and Ac-POR group. Mice in POR and Ac-POR groups received a gastric gavage of Tripterygium wilfordii polyglycoside suspension of 50 mg/kg-1 once a day for 14 consecutive days. Ac was applied at “Shenting” (DU 24), “Guanyuan” (CV 4), “Zusanli” (ST 36), and “Shenshu” (BL 23) in the Ac-POR group for 10 min per session, once a day for 14 consecutive days. All four groups were stimulated with pregnant mare serum gonadotropin and human chorionic gonadotropin, and the number of retrieved oocytes and proportion of mature oocytes were recorded. The DNA methylation level in a single mouse oocyte in each group was analyzed using single-cell genome-wide bisulfite sequencing (scBSseq), and key pathways were identified using GO and KEGG enrichment analyses. Results: A dissecting microscope revealed that the Ac therapy improved the number of retrieved oocytes compared with the POR group (p < 0.05). ScBS-seq showed that there was no significant change in global DNA methylation levels between the POR model and control group mice. However, differences were primarily observed in the differentially methylated regions (DMRs) of each chromosome, and Ac decreased global DNA methylation. DMR analysis identified 13 genes that may be associated with Ac treatment. Cdk5rap2 and Igf1r, which mediate germ cell apoptosis, growth, and development, maybe most closely related to the Ac treatment of POR. KEGG analysis revealed that differentially expressed genes were mainly enriched in Wnt, GnRH, and calcium signaling pathways. The genes were closely related to the regulation of POR via Ac. Conclusion: The results suggest that DNA methylation in oocytes is related to the development of POR and that the role of Ac in affecting DNA methylation in oocytes is associated with the Wnt, GnRH, and calcium signaling pathways as well as Cdk5rap2 and Igf1r in POR mice.

Diminazene Aceturate, an ACE2 activator, ameliorates testicular injury in diet-induced obese mice.

DIZE improved obesity and metabolic disturbances in DIO mice. An increase of sperm account and motility, along with improved morphology and increased male fertility was observed after DIZE treatment. Both serum and intratesticular testosterone levels showed an increase. Moreover, ACE2/Ang 1-7/MasR protein levels in the testes were restored, which inhibited germ cells apoptosis, lipid accumulation, and oxidative stress, and elevated testosterone synthesis-related proteins. However, the MasR antagonist A779 partially counteracted the improving effects of DIZE on metabolism and the testes of DIO mice. Conclusion: DIZE treatment has protective effects against obesity-induced testicular injury by activating ACE2/Ang 1-7/MasR axis.

Progress in the Study of TAp73 and Sperm Apoptosis.

The study of the mechanism of oligoasthenospermia, which is a major cause of male infertility, has been the focus of research in the field of male reproduction. TAp73, a member of the p53 family of oncogenes, is endowed with tumor-suppressing activity due to its structural and functional homology with p53. It has been found that TAp73, plays a key role in spermatogenesis and maintaining male reproduction. When TAp73 is low-expressed or absent, the process of spermatogenesis is severely impaired, and mice deficient in TAp73 exhibit spermatogonial DNA damage, disturbed apical cytoplasmic specialization, and spermatocyte malformations resulting in reduced male fertility. Nevertheless, when TAp73 is overexpressed, it not only drives exogenous death receptors to regulate germ cell apoptosis, but also interacts with its various substrate proteins to promote the translocation of cytoplasmic Bax proteins to the mitochondria, resulting in the upregulation of the Bax/Bcl-2 ratio on the mitochondrial membrane and triggering a series of mitochondrial apoptotic effects. In this article, we will analyze the mechanism of TAp73 and sperm apoptosis, and elaborate the mechanism of TAp73 upregulation, exogenous apoptosis pathway and mitochondrial apoptosis pathway to systematically explain that the process of apoptosis induced by high expression of TAp73 is not fixed and single, but is interconnected, so as to provide a basis for the treatment of oligoasthenospermia and the research and development of new drugs using TAp73 as a target.

Exposure to titanium dioxide nanoparticles disrupts the BTB by interfering with the assembly of stress granules in germ cells.

Titanium dioxide nanoparticles (TiO2 NPs) are among the most prevalent nanomaterials utilized in industrial and medical fields. However, their impact on spermatogenesis and male fertility remains insufficiently characterized. This study addresses the reproductive toxicity of TiO2 NPs and elucidates the underlying molecular mechanisms involved. Our findings demonstrate that exposure to TiO2 NPs leads to a significant reduction in sperm count and motility. Specifically, TiO2 NPs disrupt the integrity of the blood-testis barrier (BTB) and compromise the cytoskeletal structure in both spermatogenic and Sertoli cells. Additionally, treatment with TiO2 NPs is associated with cell death and a decrease in the protein levels of BTB-related components, including N-cadherin, β-catenin, occludin, and ZO-1. Mechanistic investigations reveal that TiO2 NPs inhibit stress granule formation in germ cells subjected to heat stress and promote germ cell apoptosis via activation of the ATM/P53 signaling pathway. Collectively, our study highlights a potential connection between environmental health and reproductive health, revealing multiple detrimental effects of TiO2 NPs and uncovering previously unrecognized mechanisms by which nanomaterials may adversely impact the reproductive system.

Beneficial effects of pentoxifylline on spermatogenesis and germ cell apoptosis in stallions subjected to scrotal heat stress

This study evaluated the effects of oral pentoxifylline on testicular biometry, histology, and gene expression in stallions subjected to scrotal heat stress. Fourteen stallions were divided into three groups: Control (CRL, n = 4), Testicular Degeneration (DEG, n = 5), and Testicular Degeneration Treated with Pentoxifylline (DEG + PTX, n = 5). Testicular degeneration was induced by scrotal insulation, twice daily, over two consecutive days (D-1 and D0). Starting the next day (D1), oral pentoxifylline (17 mg/kg) was administered every 12 h for 30 days. Testicular biometry was measured using a caliper from D-5 to D60. On days 30 and 60, testicular biopsies were collected for histopathology and gene expression analysis of BAX, CASP8, CASP9, FAS, HSF1, and PTGS2 using RT-qPCR. Pentoxifylline reduced histological damage, with the DEG + PTX group showing less pronounced basal lamina undulation and seminiferous tubule atrophy compared to the DEG group. However, it did not fully prevent lesions like germ cell vacuolization, which was reflected macroscopically by a reduction in testicular volume in both degenerated groups. The protective effects of pentoxifylline on testicular tissue can be attributed to its ability to reduce BAX expression, prevent CASP8 and CASP9 activation, and promote cellular protective mechanisms through HSF1 activation at D30. These results highlight pentoxifylline’s potential as a therapeutic agent for equine testicular damage due to scrotal heat stress, suggesting the need for further research on optimal dosage and treatment duration.

The impact of N-acetylcysteine on hypoxia-induced testicular apoptosis in male rats: TUNEL and IHC findings

The present study aimed to evaluate the impact of N-acetylcysteine (NAC) on testicular hypoxia caused by varicocele, focusing specifically on the regulation of genes related to apoptosis and oxidative stress in the testes of mature Wistar rats.Thirty-two rats were divided into four groups: Control (Sham), hypoxia, testicular hypoxia treated with NAC (Hypoxia + NAC), and healthy animals treated with NAC. After the 8-week treatment period, testicular histopathology and the levels of oxidative stress markers—superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA)—in serum were examined. The expression of Bax and Bcl-2 mRNA was analyzed using immunocytochemistry and RT-qPCR assays, while the apoptosis rate was determined using the TUNEL method.Histopathological evaluations showed that parameters such as Johnsen's score, epithelium width, and seminiferous tubule diameter indicated significant improvement in the Hypoxia + NAC group compared to the Hypoxia group. NAC administration resulted in elevated serum levels of GPx and SOD, accompanied by a reduction in MDA levels (p < 0.003). Furthermore, the study revealed that NAC decreased Bax expression and enhanced Bcl-2 gene and protein expression compared to the varicocele group (p < 0.05). Additionally, NAC administration significantly decreased the rate of apoptosis in germ cells (p < 0.05).These findings suggest that NAC administration can mitigate testicular damage induced by hypoxia from varicocele in rats, primarily due to its antioxidant properties.

Reproductive Toxicity and Multi/Transgenerational Effects of Emerging Pollutants on C. elegans.

Emerging pollutants (EPs) are receiving increasing attention due to the threats they pose to the environment and human health. As EPs continue to emerge, risk assessment requires many model animals. Caenorhabditis elegans (C. elegans) has been an outstanding toxicological model organism due to its growth and development characteristics. Particularly, in studying the transgenerational influences of EPs, C. elegans has advantages in saving time and cost due to its short generation cycle. As infertility has become a major problem in human reproductive health, reproductive toxicities of EPs on contemporary nematodes and across generations of C. elegans were introduced in this review. Moreover, the underlying mechanisms involved in germ cell apoptosis, spermatogenesis, and epigenetic alteration were discussed. Future research opportunities and challenges are also discussed to expand our understanding of the reproductive influences of EPs.

RNA-binding protein IGF2BP1 is required for spermatogenesis in an age-dependent manner.

Post-transcriptional regulation mediated by RNA binding proteins is crucial for male germline development. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), an RNA binding protein, is specifically expressed in human and mouse male gonads and is involved in manifold biological processes and tumorigenesis. However, the function of IGF2BP1 in mammalian spermatogenesis remains poorly understood. Herein, we generated an Igf2bp1 conditional knockout mouse model using Nanos3-Cre. Germ cell deficiency of Igf2bp1 in mice caused spermatogenic defects in an age-dependent manner, resulting in decreased numbers of undifferentiated spermatogonia and increased germ cell apoptosis. Immunoprecipitation-mass spectrometry analysis revealed that ELAV-like RNA binding protein 1, a well-recognized mRNA stabilizer, interacted with IGF2BP1. Single cell RNA-sequencing showed distinct mRNA profiles in spermatogonia from conditional knockout versus wide type mice. Further research showed that IGF2BP1 plays a vital role in the modulation of spermatogenesis by regulating Lin28a mRNA, which is essential for clonal expansion of undifferentiated spermatogonia. Thus, our results highlight the crucial effects of IGF2BP1 on spermatogonia for the long-term maintenance of spermatogenesis.

BCL-2 and BAX expression and germ cell apoptosis following the intervention of 1-isothiocyanato-4-methylsulfinylbutane in cisplatin-induced testicular toxicity and sperm DNA fragmentation in Sprague-Dawley rat

Cisplatin (CP) has been used in clinical oncology but causes spermatogenesis damage. Isothiocyanato-4-methylsulfonylbutane (SFN) is a potent dietary bioactive agent that has been extensively studied for its effects on disease prevention. This study focused on the intervention of SFN on Germ cell apoptosis in CP-induced testicular toxicity and sperm DNA fragmentation (SDF). A total of ninety (90) male and ninety (90) female rats (weighing, 150–200 g, 12–14 weeks old) were assigned randomly into nine groups of ten (n = 10) rats each. Group A received normal saline, group B received a single dose of 10 mg/kg CP (i.p.), group C received 50 mg/kg bwt of SFN, group D received 100 mg/kg bwt of SFN, group E received 10 mg/kg bwt CP and 50 mg/kg bwt of SFN, group F received 10 mg/kg bwt CP and 100 mg/kg bwt of SFN, group G received 10 mg/kg bwt CP and 50 mg/kg bwt vitamin C, group H received 50 mg/kg bwt of SFN and 10 mg/kg bwt CP, Group I received 100 mg/kg bwt of SFN and 10 mg/kg bwt CP. The procedure lasted for 56 days. At the end of each treatment, the 90 male rats were introduced to the 90 female rats on the proestrus at a ratio of 1:1 for fertility tests. Testicular histopathological, apoptotic marker, immunoreactivity, sperm parameters, and SDF were investigated.Cisplatin significantly decreases chromatin condensation/de-condensation levels, haploid germ cells, the number of fetuses, and BCL-2 expression. Also, CP increases SDF and BAX expression relative to control. Treatment with SFN increased BCL-2 expression, haploid germ cells, protected sperm chromatin condensation, improved microarchitecture of testes, and decreased SDF and BAX expression.Therefore, SFN protects against CP-induced apoptosis by controlling BCL-2 and BAX expression and ameliorates SDF.

Aspirin enhances radio/chemo-therapy sensitivity in C. elegans by inducing germ cell apoptosis and suppresses RAS overactivated tumorigenesis via mtROS-mediated DNA damage and MAPK pathway

Previous studies have demonstrated that combination therapy involving radiotherapy and aspirin decreases the survival rate of cancer cells. However, the mechanism by which aspirin exerts its radiation sensitization effect at the in vivo level remains largely unclear. In this study, we employed Caenorhabditis elegans (C. elegans) as a model organism to investigate the effect of aspirin combined with radio/chemo-therapy on tumors at the individual level. Here, we illustrate that high-dose aspirin increases the expression of genes involved in core apoptosis pathways (egl-1, ced-9, ced-4 and ced-3) and induces germ cell apoptosis in C. elegans through mitochondrial outer membrane permeabilization (MOMP) and elevation of reactive oxygen species (ROS) levels. Crucially, aspirin-induces ROS upregulates the expression of genes critical for DNA damage response (hus-1, clk-2 and cep-1) and genes involved in MAPK pathways (lin-45, mek-2, mpk-1, sek-1 and pmk-1), thereby mediating the enhanced sensitivity of radio/chemo-therapy by aspirin. Notably, aspirin fails to induce germ cell apoptosis and enhance radio/chemo-therapy in C. elegans lacking the expression of each of those genes. Furthermore, in a C. elegans tumor-like symptom model, aspirin enhances radio/chemo-therapy sensitivity through ROS induction. However, low-dose aspirin can diminish the apoptotic signal of reproductive cells in C. elegans and exert anti-inflammatory effects. Our research results suggest that the tumor-suppressive and radio/chemo-therapy sensitizing effects of aspirin provide robust experimental evidence for improving the clinical efficacy of tumor radio/chemo-therapy and deepening our understanding of aspirin's mechanism of action in cancer.

Molecular mechanisms underlying the effects of hypo- and hyper-prolactinemia on spermatogenesis and fertility in male rats.

Hypo- and hyper-prolactinemia have deleterious effects on male reproduction, yet there is a dearth of information regarding the underlying mechanisms. The aim of this study was to delineate the molecular mechanisms by which hypo- and hyper-prolactinemia affects spermatogenesis and fertility in male rats. In vivo male rat models for hypo- and hyper-prolactinemia were established using dopamine receptor agonist, Bromocriptine (Brm), and antagonist, Fluphenazine (Flu), respectively. Effects on fertility and spermatogenesis were assessed by studying pre- and post-implantation loss, litter size, sperm parameters, hormonal profile, testicular histology, testicular cell population, and testicular transcriptome in rats. Treatment with Brm and Flu for 60 days led to subfertility, which was indicated by an increase in pre- and post-implantation loss and decrease in litter size, when mated with control female rats. Decreased sperm count was observed after both treatments, whereas reduced sperm motility was noted in Flu group. Serum FSH was unaffected, and LH was decreased by Flu treatment. Testosterone was decreased in both the groups, whereas estradiol was decreased in the Flu group. An arrest in spermatogenic cycle beyond round spermatids was observed in the Flu group. Additionally, testicular apoptosis in germ cells, mostly spermatocytes of Stage IX-XIV was noted in both the groups. Further, testicular RNA-Seq analysis revealed a total of 1539 and 824 differentially expressed genes/DEGs in Brm and Flu, respectively (Sequence Read Archive/SRA Database accession number: PRJNA1150513). Gene ontology and pathway analysis of DEGs highlighted enrichment of steroid metabolic pathway and ribosomal biogenesis pathway. Hub genes identified from the DEGs were validated by qPCR and the results showed that Uba52, Rps27a, Rpl23, Rps5, Rps16 were significantly down-regulated by Brm, whereas Rps27a, Rps29, Rps15, Rps27, Faul1 were significantly down-regulated by Flu. Hypo- and hyper-prolactinemia leads to subfertility and decreased sperm parameters possibly through an effect on steroid metabolism and ribosomal biogenesis pathway. Therefore, maintaining prolactin levels in physiological range is crucial.

Deficiency in the Rab25 gene leads to a decline in male fertility and testicular injury: Impact on the regulation of germ cell proliferation and apoptosis

BackgroundRab25 is a member of the Rab family, functioning as a regulatory molecule in intracellular transport. Although its involvement in cellular functions and disease development is well-established, its precise roles in male reproductive physiology remain elusive. MethodsTo explore the specific roles of Rab25 in testicular development and spermatogenesis, we established the Rab25−/− mouse model and Rab25 knockdown germ cell line (GC-2). We compared the fertility, sperm analysis, and testicular tissues between Rab25−/− and wild-type male mice. To delve deeper into potential mechanisms, we employed immunohistochemistry, TUNEL assay, Western Blotting, CCK-8 assay, etc. to evaluate cell proliferation and apoptosis in testicular tissues and GC-2 cells. ResultsOur findings indicated that Rab25 was expressed in germ cells and Leydig cells in the testes. Although the weight of Rab25−/− mice testes exhibited no significant changes, fertility was compromised, with a decrease in sperm quantity and reduced motility. HE staining revealed a disorganized arrangement of germ cells and vacuolization. Additionally, chromatin marginalization and nuclear pyknosis were observed in the Rab25−/− mice. In both Rab25−/− mice testes and Rab25 knockdown GC-2 cells, we found that germ cell proliferation was reduced, while apoptosis was increased. ConclusionsIn conclusion, our study proposes that Rab25 plays a vital role in spermatogenesis by regulating the proliferation and apoptosis of germ cells.

Exposure to benzyl butyl phthalate (BBP) leads to increased double-strand break formation and germline dysfunction in Caenorhabditis elegans.

Benzyl butyl phthalate (BBP), a plasticizer found in a wide range of consumer products including vinyl flooring, carpet backing, food packaging, personal care products, and children's toys, is an endocrine-disrupting chemical linked to impaired reproduction and development in humans. Despite evidence that BBP exposure perturbs the integrity of male and female gametes, its direct effect on early meiotic events is understudied. Here, using the nematode Caenorhabditis elegans, we show that BBP exposure elicits a non-monotonic dose response on the rate of X-chromosome nondisjunction measured using a high-throughput screening platform. From among the range of doses tested (1, 10, 100 and 500 μM BBP), we found that 10 μM BBP elicited the strongest effect on the germline, resulting in increased germ cell apoptosis and chromosome organization defects. Mass spectrometry analysis shows that C. elegans efficiently metabolizes BBP into its primary metabolites, monobutyl phthalate (MBP) and monobenzyl phthalate (MBzP), and that the levels of BBP, MBP, and MBzP detected in the worm are within the range detected in human biological samples. Exposure to 10 μM BBP leads to germlines with enlarged mitotic nuclei, altered meiotic progression, activation of a p53/CEP-1-dependent DNA damage checkpoint, increased double-strand break levels throughout the germline, chromosome morphology defects in oocytes at diakinesis, and increased oxidative stress. RNA sequencing analysis indicates that BBP exposure results in the altered expression of genes involved in xenobiotic metabolic processes, extracellular matrix organization, oocyte morphogenesis, meiotic cell cycle, and oxidoreduction. Taken together, we propose that C. elegans exposure to BBP leads to increased oxidative stress and double-strand break formation, thereby compromising germline genomic integrity and chromosome segregation.

Arecoline Hydrobromide Promotes the Apoptosis of Male Germ Cells

Arecoline Hydrobromide Promotes the Apoptosis of Male Germ Cells

Immunohistological Assessment of Male Germ Cell Apoptosis, and Histological Observation of Seminiferous Tubules and Epididymides According to Temporal Testicular Regulation in the Large Japanese Field Mouse (Apodemus speciosus )

Immunohistological Assessment of Male Germ Cell Apoptosis, and Histological Observation of Seminiferous Tubules and Epididymides According to Temporal Testicular Regulation in the Large Japanese Field Mouse <i>(Apodemus speciosus )</i>

Nutritional vitamin B12 regulates RAS/MAPK-mediated cell fate decisions through one-carbon metabolism

Vitamin B12 is an essential nutritional co-factor for the folate and methionine cycles, which together constitute one-carbon metabolism. Here, we show that dietary uptake of vitamin B12 modulates cell fate decisions controlled by the conserved RAS/MAPK signaling pathway in C. elegans. A bacterial diet rich in vitamin B12 increases vulval induction, germ cell apoptosis and oocyte differentiation. These effects are mediated by different one-carbon metabolites in a tissue-specific manner. Vitamin B12 enhances via the choline/phosphatidylcholine metabolism vulval induction by down-regulating fat biosynthesis genes and increasing H3K4 tri-methylation, which results in increased expression of RAS/MAPK target genes. Furthermore, the nucleoside metabolism and H3K4 tri-methylation positively regulate germ cell apoptosis and oocyte production. Using mammalian cells carrying different activated KRAS and BRAF alleles, we show that the effects of methionine on RAS/MAPK-regulated phenotype are conserved in mammals. Our findings suggest that the vitamin B12-dependent one-carbon metabolism is a limiting factor for diverse RAS/MAPK-induced cellular responses.

Benzo(a)pyrene exposure during pregnancy leads to germ cell apoptosis in male mice offspring via affecting histone modifications and oxidative stress levels

Infertility has gradually become a global health concern, and evidence suggests that exposure to environmental endocrine-disrupting chemicals (EDCs) represent one of the key causes of infertility. Benzo(a)pyrene (BaP) is a typical EDC that is widespread in the environment. Previous studies have detected BaP in human urine, semen, cervical mucus, oocytes and follicular fluid, resulting in reduced fertility and irreversible reproductive damage. However, the mechanisms underlying the effects of gestational BaP exposure on offspring fertility in male mice have not been fully explored. In this study, pregnant mice were administered BaP at doses of 0, 5, 10 and 20 mg/kg/day via gavage from Days 7.5 to 12.5 of gestation. The results revealed that BaP exposure during pregnancy disrupted the structural integrity of testicular tissue, causing a disorganized arrangement of spermatogenic cells, compromised sperm quality, elevated levels of histone modifications and increased apoptosis in the testicular tissue of F1 male mice. Furthermore, oxidative stress was also increased in the testicular tissue of F1 male mice. BaP activated the AhR/ERα signaling pathway, affected H3K4me3 expression and induced apoptosis in testicular tissue. AhR and Cyp1a1 were overexpressed, and the expression of key molecules in the antioxidant pathway, including Keap1 and Nrf2, was reduced. The combined effects of these molecules led to apoptosis in testicular tissues, damaging and compromising sperm quality. This impairment in testicular cells further contributed to compromised testicular tissues, ultimately impacting the reproductive health of F1 male mice.