Enhanced electrophysiological activity and neurotoxicity screening of environmental chemicals using 3D neurons from human neural precursor cells purified with PSA-NCAM.

The assessment of neurotoxicity for environmental chemicals is of utmost importance in ensuring public health and environmental safety. Multielectrode array (MEA) technology has emerged as a powerful tool for assessing disturbances in the electrophysiological activity. Although human embryonic stem cell (hESC)-derived neurons have been used in MEA for neurotoxicity screening, obtaining a substantial and sufficiently active population of neurons from hESCs remains challenging. In this study, we successfully differentiated neurons from a large population of human neuronal precursor cells (hNPC) purified using a polysialylated neural cell adhesion molecule (PSA-NCAM), referred to as hNPCPSA-NCAM+. The functional characterization demonstrated that hNPCPSA-NCAM+-derived neurons improve functionality by enhancing electrophysiological activity compared to total hNPC-derived neurons. Furthermore, three-dimensional (3D) neurons derived from hNPCPSA-NCAM+ exhibited reduced maturation time and enhanced electrophysiological activity on MEA. We employed subdivided population analysis of active mean firing rate (MFR) based on electrophysiological intensity to characterize the electrophysiological properties of hNPCPSA-NCAM+-3D neurons. Based on electrophysiological activity including MFR and burst parameters, we evaluated the sensitivity of hNPCPSA-NCAM+-3D neurons on MEA to screen both inhibitory and excitatory neuroactive environmental chemicals. Intriguingly, electrophysiologically active hNPCPSA-NCAM+-3D neurons demonstrated good sensitivity to evaluate neuroactive chemicals, particularly in discriminating excitatory chemicals. Our findings highlight the effectiveness of MEA approaches using hNPCPSA-NCAM+-3D neurons in the assessment of neurotoxicity associated with environmental chemicals. Furthermore, we emphasize the importance of selecting appropriate signal intensity thresholds to enhance neurotoxicity prediction and screening of environmental chemicals.

Housing insecurity and employment stability: An investigation of working mothers.

Little evidence informs the relationship between housing insecurity and employment for working mothers. The present study aimed to identify variation in work schedules and supports, as well as the link from housing insecurity to employment experiences in a sample of at-risk mothers. Latent class analysis identified subtypes of employment stability; multinomial logistic regression estimated links from housing insecurity to class membership. Three subtypes of employment stability emerged, "Full-Time and Stable," "Full-Time and Unstable," and "Part-Time Weekend." Housing insecurity increased risk for being in the "Unstable" class relative to the other classes such that these mothers experienced stressful work schedules that offered little support or flexibility for family and child needs. Identifying and intervening on housing insecurity can promote stable employment. Increased workplace supports such as paid leave, flexible schedules, and antidiscrimination training can better enable mothers to juggle the competing demands of motherhood and work.

Impedance Measurement System for Assessing the Barrier Integrity of Three-Dimensional Human Intestinal Organoids.

Human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) hold unprecedented promise for basic biology and translational applications. However, developing a quantitative method to evaluate the epithelial cell membrane integrity of HIOs as an in vitro intestinal barrier model is a major challenge because of their complex three-dimensional (3D) structure. In this study, we developed an impedance system to measure the change in electrical resistance of 3D HIOs depending on the integrity of the intestinal epithelial cell membrane, which can reflect functionality and maturity. The expression of intestinal maturation- and tight junction-related markers was significantly higher in HIOs matured in vitro by treatment with IL-2 than in control HIOs. Analysis of gap junction size indicated that mature HIOs have greater integrity, with approximately 30% more compact gaps than immature HIOs. We designed a multi-microchannel system controlled by the inhalation pressure where the HIO is loaded, which enhances the stability and sensitivity of the impedance signal. We demonstrated the applicability of the impedance system by showing the difference in resistance between control and mature HIOs, reflecting the expression of tight junction proteins and their maturation status. We also validated the impedance system by monitoring its resistance in real time during junctional damage to HIOs induced by a digestive agent. In summary, we suggest a quantitative method to directly quantify the physiological changes in complex 3D organoid structures based on impedance spectroscopy, which can be applied to noninvasively monitor live cells and therefore enable their use in subsequent experiments.

Construction of a non-contact community treatment centre for asymptomatic and mildly symptomatic COVID-19 patients during the COVID-19 pandemic.

The explosive outbreak of COVID-19 led to a shortage of medical resources, including isolation rooms in hospitals, healthcare workers (HCWs) and personal protective equipment. Here, we constructed a new model, non-contact community treatment centres to monitor and quarantine asymptomatic and mildly symptomatic COVID-19 patients who recorded their own vital signs using a smartphone application. This new model in Korea is useful to overcome shortages of medical resources and to minimise the risk of infection transmission to HCWs.

Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney.

Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers. In this study, the toxicity of ifosfamide was evaluated using single-and multiple-dose intraperitoneal administration in rats under Good Laboratory Practice guidelines, and an additional microarray experiment was followed to support toxicological findings. A single dose of ifosfamide (50 mg/kg) did not induce any pathological changes. Meanwhile, severe renal toxicity was observed in the 7 and 28 days consecutively administered groups, with significant increases in blood urea nitrogen and creatinine levels. In the tox-list analysis, cholesterol synthesis-related genes were mostly affected in the liver and renal failure-related genes were affected in the kidney after ifosfamide administration. Moreover, interferon regulatory factor 7 was selected as the main upstream regulator that changed in both the liver and kidney, and was found to interact with other target genes, such as ubiquitin specific peptidase 18, radical S-adenosyl methionine domain containing 2, and interferon-stimulated gene 15, which was further confirmed by real-time RT-PCR analysis. In conclusion, we confirmed kidney-biased ifosfamide organ toxicity and identified identically altered genes in both the liver and kidney. Further comprehensive toxicogenomic studies are required to reveal the exact relationship between ifosfamide-induced genes and organ toxicity.

Competition Among Mental Health Organizations: Environmental Drivers and Strategic Responses.

While mental health system reforms have sought to leverage competition in the private sector to improve service quality and costs, competition among mental health organizations is poorly understood. To inform future studies about the impact of policy and system reforms on mental health organizations and service delivery, this qualitative study explores (1) resources for which organizations compete most intensively, (2) drivers of competition, and (3) leaders' strategic organizational responses. Semi-structured phone interviews were conducted with 15 organizational leaders (CEO's, executive directors) representing about 22% of organizations in the regional mental health market. Interviews covered leaders' perceptions about competition, and their strategic responses. Porter's seminal framework on competition was used to interpret codes and themes. Intensive competition for personnel was driven by workforce shortages, new for-profit organizations, and alternative employment opportunities. In response, organizations have attended to wages/benefits, recruitment, and retention. However, strong community need, expanded insurance coverage, and a history of local strategic responses that created service niches appeared to have minimized competition for financial resources in the region. Competition for funding and clients was expected to intensify under systems reform, and in anticipation, organizations were expanding services. Leaders also feared for the viability of smaller organizations in highly competitive environments. Consistent with theory on competition, mental health organizations compete and respond in ways that might improve services. However, the goals of privatization may have been unrealized because of minimal competition for funding and clients, and intense competition may undermine quality.

Facility and Family Communication during the COVID-19 Visit Restriction: Early Perspectives of Family Members.

During the COVID-19 pandemic, family concerns regarding residents in long-term care facilities (LTCFs) increased due to a high proportion of COVID cases and deaths among residents and restrictions that made it impossible to visit. These changes created numerous challenges for facilities communicating with families, and between families and residents. However, little is known about how these facilities addressed these communication challenges and how those communication strategies were related to family perceptions about the facility. We implemented an online survey of family members or friends of residents in LTCFs from April 28 to June 19, 2020, using convenience sampling. A total of 174 responses nationwide reported the types of communications used, frequency of communication and alternative visits, and whether respondents had peace of mind, would recommend the facility, or were considering removing the resident from the facility. The results of our hierarchical logistic regression showed that respondents felt greater peace of mind when there were multiple communication channels to contact the resident. Also, respondents had more negative perceptions of a facility when they were not informed about confirmed COVID cases. Our findings suggest multiple communication channels and transparency about COVID status were effective in keeping positive family perceptions about the facility.

Comparative omics analyses of hepatotoxicity induced by oral azole drugs in mice liver and primary hepatocytes.

Ketoconazole (KTZ) and itraconazole (ITZ) are antifungal agents that have a broad spectrum of activity against fungal pathogens. However, the therapeutic indications of many antifungal drugs, including those of the azole group, are restricted due to possible hepatotoxicity. We performed toxicogenomic analyses using in vivo and in vitro models to investigate the molecular mechanisms underlying the hepatotoxicity of two azole antifungal drugs. C57BL/6 male mice were treated daily with KTZ or ITZ, sacrificed at days 1 or 7, and the serum biochemistry and histopathology results showed that the KTZ-treated mice exhibited hepatotoxicity. Primary hepatocytes from C57BL/6 mice also exposed to KTZ or ITZ, and the cytotoxic effects of KTZ and ITZ were evaluated; KTZ exerted a greater cytotoxic effect than ITZ. The gene expression profiles in the livers of the 7-day-treated group and primary hepatocytes of the 24-h-treated group for both KTZ and ITZ were comparatively analyzed. Differentially expressed genes were selected based on the fold-changes and statistical significance, and the biological functions were analyzed using ingenuity pathways analysis. The results revealed that genes related to cholesterol synthesis were overexpressed in the liver in the KTZ-treated group, whereas expression of those related to acute phase injury was significantly altered in the ITZ-treated group. Causal gene analyses suggested that sterol regulatory element-binding transcription factors are key regulators that activate the transcription of target genes associated with the hepatotoxicity induced by oral KTZ. These findings enhance our understanding of the molecular mechanisms underlying the hepatotoxicity of azole drugs.

Identifying candidates for gamma knife radiosurgery among elderly patients with brain metastases.

We investigated the outcomes of gamma knife radiosurgery (GKRS) for elderly patients (≥ 65 years) with brain metastases, and identified survival-associated factors. We retrospectively analyzed data from 115 patients treated with GKRS for 1-15 brain metastases. The median patient age was 72 years; most primary tumors were pulmonary (n = 83). The mean lesion volume was 2.1 ± 4.8 mL. A mean dose of 19.3 Gy was delivered to the mean 63.9% isodose line. The median overall survival (OS) was 5.3 months (95% confidence interval [CI] 3.5-7.1). During follow-up (median, 5.1 months), 91 patients died of primary cancer progression while 1 died of unknown causes. The 6- and 12-month local control rates were 94.9 and 88.1%, respectively. On multivariate analysis, female sex (p = 0.005, hazard ratio [HR] 0.533, 95% CI 0.343-0.827) and a controlled primary tumor (p < 0.001, HR 0.328, 95% CI 0.180-0.596) were significantly favorable prognostic factors. Of non-small cell lung cancer patients with EGFR mutations, 76.5% were women (p = 0.005). The median OS of EGFR-mutant and EGFR-wildtype patients were 19.1 and 4.7 months, respectively (p = 0.080). Brain metastases < 3 mL showed better local control rates after GKRS (p = 0.005). GKRS produces favorable outcomes in women with brain metastases who are ≥ 65 years and have controlled primary tumors. Such patients are therefore suitable candidates for GKRS.

Validation of Prostate Imaging Reporting and Data System Version 2 Using an MRI-Ultrasound Fusion Biopsy in Prostate Cancer Diagnosis.

OBJECTIVE: The purpose of our study was to prospectively assess Prostate Imaging Reporting and Data System (PI-RADS) version 2 using an MRI-ultrasound fusion biopsy. SUBJECTS AND METHODS: This study included 295 consecutive patients with 478 lesions who underwent multiparametric MRI and subsequent MRI-ultrasound fusion biopsy between December 2014 and September 2016. Lesions were assessed by using an overall score of PI-RADS version 2. One radiologist assessed the presence or absence of clinically significant prostate cancer in the whole gland and in subgroups of the peripheral zone and transition zone by using cutoff values of ≥ 4 and ≥ 3. Histologic examination of MRI-ultrasound fusion biopsy specimens was used as the reference standard. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated to assess the utility of PI-RADS version 2 for the diagnosis of clinically significant prostate cancer. RESULTS: The overall PI-RADS version 2 scores showed an accuracy of 82.2% (393/478) for the whole gland, with a cutoff value of ≥ 4 granting sensitivity of 90.0% (90/100), specificity of 80.1% (303/378), PPV of 83.3% (90/108), and NPV of 81.8% (303/370). The overall scores showed accuracies of 84.7% (301/355) in the peripheral zone and 74.7% (92/123) in the transition zone. When we applied an arbitrary overall score of ≥ 3, accuracy was 68.6% (328/478), sensitivity was 94.6% (124/131), specificity was 58.7% (204/347), PPV was 51.6% (124/240), and NPV was 85.7% (204/238). CONCLUSION: PI-RADS version 2 has an overall good performance for the diagnosis of clinically significant prostate cancer.

Frequency of MED12 mutations in phyllodes tumors: Inverse correlation with histologic grade.

Phyllodes tumor (PT) is a rare breast biphasic tumor with a potential risk of recurrence and metastasis. In this study, the frequency of MED12 mutations in 176 PTs (49 benign, 49 borderline, and 78 malignant) was determined and the prognostic effect of these mutations in malignant type PT was evaluated. Analysis of MED12 mutations was performed by Sanger sequencing targeting the hotspot mutation region (exon 2) of MED12. Immunohistochemistry was also applied for evaluation of MED12 protein expression on tissue microarray blocks for 133 PTs including 50 benign, 50 borderline, and 33 malignant cases. A notable difference in the frequency of MED12 mutations was found according to histologic grade (71.4% of benign PTs, 51% of borderline PTs, 26.9% of malignant PTs; P < 0.001). MED12 protein expression was not correlated with MED12 mutation status. Patients with malignant PTs that harbored MED12 mutations demonstrated improved disease-free survival (DFS) compared with those without MED12 mutation (P = 0.07). MED12 mutation was a common molecular alteration in PT and the frequency of MED12 mutation decreased with increasing histologic grade. In malignant PT, MED12 exon 2 mutations showed improved DFS but without significance. © 2016 Wiley Periodicals, Inc.

Integrative analysis of genes and miRNA alterations in human embryonic stem cells-derived neural cells after exposure to silver nanoparticles.

Given the rapid growth of engineered and customer products made of silver nanoparticles (Ag NPs), understanding their biological and toxicological effects on humans is critically important. The molecular developmental neurotoxic effects associated with exposure to Ag NPs were analyzed at the physiological and molecular levels, using an alternative cell model: human embryonic stem cell (hESC)-derived neural stem/progenitor cells (NPCs). In this study, the cytotoxic effects of Ag NPs (10-200µg/ml) were examined in these hESC-derived NPCs, which have a capacity for neurogenesis in vitro, at 6 and 24h. The results showed that Ag NPs evoked significant toxicity in hESC-derived NPCs at 24h in a dose-dependent manner. In addition, Ag NPs induced cell cycle arrest and apoptosis following a significant increase in oxidative stress in these cells. To further clarify the molecular mechanisms of the toxicological effects of Ag NPs at the transcriptional and post-transcriptional levels, the global expression profiles of genes and miRNAs were analyzed in hESC-derived NPCs after Ag NP exposure. The results showed that Ag NPs induced oxidative stress and dysfunctional neurogenesis at the molecular level in hESC-derived NPCs. Based on this hESC-derived neural cell model, these findings have increased our understanding of the molecular events underlying developmental neurotoxicity induced by Ag NPs in humans.

Low-risk prostate cancer: the accuracy of multiparametric MR imaging for detection.

PURPOSE: To retrospectively determine diagnostic performance with multiparametric magnetic resonance (MR) imaging for detection of cancer of different tumor volumes and Gleason grades in patients with clinically low-risk prostate cancer. MATERIALS AND METHODS: The local ethical committee and institutional review board approved this study. Consecutive patients with clinically determined low-risk cancer (n = 100) were examined with multiparametric MR imaging (T2 weighted, diffusion weighted, and dynamic contrast material enhanced) by using a 3.0-T imager before prostatectomy. Two radiologists independently assessed the likelihood of cancer per sextant. Cancers with a volume of 0.5 cm(3) or more identified at histopathologic examination were compared with multiparametric MR images. Cancer detection with multiparametric MR imaging was assessed for tumors of different volumes and Gleason grades by using a logistic generalized estimating equation model with 95% confidence intervals (CIs) with two optimal dichotomized cutoff scores. RESULTS: For cancers greater than or equal to 0.5 cm(3), with respect to cancer volume and Gleason grade, multiparametric MR imaging showed high diagnostic performance for the detection of cancer. Diagnostic accuracy with multiparametric MR imaging was significantly higher for cancers with a volume greater than 1 cm(3) than for those with a volume of 0.5-1 cm(3) (87.7%; 95% CI: 82.4%, 94.3% vs 82.6%; 95% CI: 79.0%, 88.7%; P = .02) and for cancers with Gleason grades of 7 or more than for those with grades of 6 or less (89.2%; 95% CI: 85.4%, 93.8% vs 80.6%; 95% CI: 71.2%, 89.8%; P = .01). Detection rates for cancers with a volume more than 1 cm(3) and a Gleason grade of 7 or more were significantly higher than for those with a volume of 0.5-1 cm(3) and a Gleason grade of 6 or less(87.8%; 95% CI: 85.3%, 93.7% vs 82.0%; 95% CI: 75.6%, 86.1%; P = .01). CONCLUSION: Detection of prostate cancer in patients with clinically low-risk cancer with multiparametric MR imaging is highly accurate, and larger cancer volume and higher Gleason grade are associated with higher detection accuracy.

Nonylphenol-induced apoptotic cell death in mouse TM4 Sertoli cells via the generation of reactive oxygen species and activation of the ERK signaling pathway.

Nonylphenol (NP), a representative endocrine disruptor, interferes with reproductive function in aquatic organisms and animals. Although many previous studies have focused on apoptotic cell death by NP, the fundamental mechanism of NP on apoptosis remains poorly understood. Here, we investigated the molecular mechanism on NP-induced apoptotic cell death in mouse TM4 Sertoli cells. To evaluate NP treatment on cell viability, formazan and lactate dehydrogenase (LDH) assays were performed. Results indicate that NP reduced cell viability and increased the release of LDH in dose- and time-dependent manners. The reduction of cell viability by NP treatment appeared to involve necrosis as well as apoptosis based on nuclear fragmentation, an increase in the sub G1 population, and the detection of poly(ADP ribose) polymerase and caspase-3 cleavage. Additionally, the anti-apoptotic protein Bcl-2 diminished, whereas the pro-apoptotic protein Bax increased in a time-dependent manner. Note that NP-induced apoptotic cell death was enhanced by the generation of reactive oxygen species (ROS) and activation of extracellular signal-regulated kinase (ERK) signaling. Pretreatment with N-acetylcysteine, an antioxidant, attenuated NP-induced apoptotic cell death. Moreover, NP caused a transient activation of the MAPK pathway. In particular, NP-induced cell death was significantly suppressed by U0126, a specific inhibitor of ERK. Taken together, our results suggest that NP induces apoptosis in mouse TM4 Sertoli cells via ROS generation and ERK activation.

Disparities in the Quality of Working Life Among Older Workers: Housing Conditions and Life Satisfaction With Latent Class Analysis.

Little empirical research informs understanding of the disparate active aging experiences among working older adults, especially in terms of the association with living circumstances and life satisfaction. To address this knowledge gap, this study used latent class analysis on data from the 2020 Health and Retirement Study (HRS) core interview and focused on 1,194 employed adults aged 50 and above. The results revealed four subtypes of the quality of working life in older workers. Notably, in contrast to the other identified classes, higher levels of housing satisfaction and feelings of neighborhood safety were significantly associated with an increased likelihood of being a member of the group of older adults with the highest work capacities and the healthy work-life balance. Furthermore, participation in the class characterized by the highest work capacity and a healthy work-life balance was related to the highest levels of overall life satisfaction.

Hepa-ToxMOA: a pathway-screening method for evaluating cellular stress and hepatic metabolic-dependent toxicity of natural products.

In the field of drug discovery, natural products have emerged as therapeutic agents for diseases such as cancer. However, their potential toxicity poses significant obstacles in the developing effective drug candidates. To overcome this limitation, we propose a pathway-screening method based on imaging analysis to evaluate cellular stress caused by natural products. We have established a cellular stress sensing system, named Hepa-ToxMOA, which utilizes HepG2 cells expressing green fluorescent protein (GFP) fluorescence under the control of transcription factor response elements (TREs) for transcription factors (AP1, P53, Nrf2, and NF-κB). Additionally, to augment the drug metabolic activity of the HepG2 cell line, we evaluated the cytotoxicity of 40 natural products with and without S9 fraction-based metabolic activity. Our finding revealed different activities of Hepa-ToxMOA depending on metabolic or non-metabolic activity, highlighting the involvement of specific cellular stress pathways. Our results suggest that developing a Hepa-ToxMOA system based on activity of drug metabolizing enzyme provides crucial insights into the molecular mechanisms initiating cellular stress during liver toxicity screening for natural products. The pathway-screening method addresses challenges related to the potential toxicity of natural products, advancing their translation into viable therapeutic agents.

Safety assessment and gastrointestinal retention of orally administered cerium oxide nanoparticles in rats.

Cerium oxide nanoparticles (CeO2 NPs, NM-212) are well-known for their catalytic properties and antioxidant potential, and have many applications in various industries, drug delivery, and cosmetic formulations. CeO2 NPs exhibit strong antimicrobial activity and can be used to efficiently remove pathogens from different environments. However, knowledge of the toxicological evaluation of CeO2 NPs is too limited to support their safe use. In this study, CeO2 NPs were orally administered to Sprague Dawley rats for 13 weeks at the doses of 0, 10, 100, and 1000 mg/kg bw/day, followed by a four week recovery period. The hematology values for the absolute and relative reticulocyte counts in male rats treated with 1000 mg/kg bw/day CeO2 NPs were lower than those in control rats. The clinical chemistry values for sodium and chloride in the treated male rat groups (100 and 1000 mg/kg/day) and total protein and calcium in the treated female rat groups (100 mg/kg/day) were higher than those in the control groups. However, these changes were not consistent in both sexes, and no abnormalities were found in the corresponding pathological findings. The results showed no adverse effects on any of the parameters assessed. CeO2 NPs accumulated in the jejunum, colon, and stomach wall of rats administered 1000 mg/kg CeO2 NPs for 90 days. However, these changes were not abnormal in the corresponding histopathological and immunohistochemical examinations. Therefore, 1000 mg/kg bw/day may be considered the "no observed adverse effect level" of CeO2 NPs (NM-212) in male and female SD rats under the present experimental conditions.

Gene expression analysis of toxicological pathways in TM3 leydig cell lines treated with Ethane dimethanesulfonate.

Ethane dimethanesulfonate (EDS), a well-known alkylating agent, selectively destroys Leydig cells. To clarify the molecular pathways underlying EDS action on Leydig cells, we analyzed gene expression profiles of an EDS-treated TM3 Leydig cell line. In this study, we analyzed the representative canonical pathways and toxicity pathways/gene lists using the Ingenuity Pathways Analysis program. In TM3 cells, 677 and 6756 genes were identified as being up- or downregulated after 3 and 24 h EDS treatments, respectively, (>1.3-fold changes, p < 0.05). Toxicological pathway analysis revealed that expression of genes related to Nrf2-mediated oxidative stress response showed remarkable changes in early or later stage of EDS-treated TM3 cells. Several genes related to steroidogenesis and apoptosis were also differentially expressed at 24 h in EDS-treated TM3 cells. Overall, toxicological pathway analysis using gene expression profiling showed that oxidative stress might be an important factor in cell death in TM3 cells affected by EDS treatment.

Aß-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation.

Mitochondria in neural progenitors play a crucial role in adult hippocampal neurogenesis by being involved in fate decisions for differentiation. However, the molecular mechanisms by which mitochondria are related to the genetic regulation of neuronal differentiation in neural progenitors are poorly understood. Here, we show that mitochondrial dysfunction induced by amyloid-beta (Aß) in neural progenitors inhibits neuronal differentiation but has no effect on the neural progenitor stage. In line with the phenotypes shown in Alzheimer's disease (AD) model mice, Aß-induced mitochondrial damage in neural progenitors results in deficits in adult hippocampal neurogenesis and cognitive function. Based on hippocampal proteome changes after mitochondrial damage in neural progenitors identified through proteomic analysis, we found that lysine demethylase 5A (KDM5A) in neural progenitors epigenetically suppresses differentiation in response to mitochondrial damage. Mitochondrial damage characteristically causes KDM5A degradation in neural progenitors. Since KDM5A also binds to and activates neuronal genes involved in the early stage of differentiation, functional inhibition of KDM5A consequently inhibits adult hippocampal neurogenesis. We suggest that mitochondria in neural progenitors serve as the checkpoint for neuronal differentiation via KDM5A. Our findings not only reveal a cell-type-specific role of mitochondria but also suggest a new role of KDM5A in neural progenitors as a mediator of retrograde signaling from mitochondria to the nucleus, reflecting the mitochondrial status.

miRNA regulation of cytotoxic effects in mouse Sertoli cells exposed to nonylphenol.

BACKGROUND: It is known that some environmental chemicals affect the human endocrine system. The harmful effects of endocrine disrupting chemical (EDC) nonylphenol (NP) have been studied since the 1980s. It is known that NP adversely affects physiological functions by mimicking the natural hormone 17 beta-estradiol. In the present study, we analyzed the expression of miRNAs and their target genes in mouse Sertoli TM4 cells to better understand the regulatory roles of miRNAs on Sertoli cells after NP exposure. METHODS: Mouse TM4 Sertoli cells were treated with NP for 3 or 24 h, and global gene and miRNA expression were analyzed using Agilent mouse whole genome and mouse miRNA v13 arrays. RESULTS: We identified genes that were > 2-fold differentially expressed in NP-treated cells and control cells (P < 0.05) and analyzed their functions through Gene Ontology analysis. We also identified miRNAs that were differentially expressed in NP-treated and control cells. Of the 186 miRNAs the expression of which differed between NP-treated and control cells, 59 and 147 miRNAs exhibited 1.3-fold increased or decreased expression at 3 and 24 h, respectively. Network analysis of deregulated miRNAs suggested that Ppara may regulate the expression of certain miRNAs, including miR-378, miR-125a-3p miR-20a, miR-203, and miR-101a, after exposure to NP. Additionally, comprehensive analysis of predicted target genes for miRNAs showed that the expression of genes with roles in cell proliferation, the cell cycle, and cell death were regulated by miRNA in NP-treated TM4 cells. Levels of expression of the miRNAs miR-135a* and miR-199a-5p were validated by qRT-PCR. Finally, miR-135a* target gene analysis suggests that the generation of reactive oxygen species (ROS) following exposure to NP exposure may be mediated by miR-135a* through regulation of the Wnt/beta-catenin signaling pathway. CONCLUSIONS: Collectively, these data help to determine NP's actions on mouse TM4 Sertoli cells and increase our understanding of the molecular mechanisms underlying the adverse effects of xenoestrogens on the reproductive system.