The influences of DNA methylation and epigenetic clocks, on metabolic disease, in middle-aged Koreans.

BACKGROUND: Considering that DNA methylation (DNAm) profiles are, in large part, modifiable by lifestyle and environmental influences, it has been proposed that epigenetic clocks provide a better estimate of biological age than chronological age, as associated with current health status. Even though metabolic diseases induce precocious aging, little is known about associations between metabolic syndrome (MetS) and DNA methylation clocks, and stochastic epigenetic mutations (SEMs), in a Korean population. Therefore, we assessed four different epigenetic clocks (Pan-tissue, Hannum, PhenoAge, and GrimAge), and their accelerations, on MetS and MetS-related lifestyle factors, in Koreans. We measured genome-wide DNA methylation (485,512 CpGs), using an Illumina 450 methylation BeadChip array, with data from 349 blood samples. RESULTS: DNAm GrimAge strongly correlated with chronological age (r = 0.77, p < 0.001) compared to the other three epigenetic clocks and SEMs. DNAm-based surrogate markers, with regard to MetS, including the gene encoding plasminogen activator inhibitor-1 (PAI1), also correlated with chronological age. Within cohorts stratified by age group, sex, regional area, smoking, and alcohol drinking, a positive correlation was observed between DNAm GrimAge and chronological age (0.43 ≤ r ≤ 0.78). In particular, we identified MetS to associate with accelerated GrimAge, and age-adjusted PAI1, in the middle-age group. Accerelated GrimAge also associated with risk of MetS in the middle-age group (odds ratio = 1.16, p = 0.046), which appears to mediate their associations with fasting glucose. Multiple linear regression showed that DNAm GrimAge, and its acceleration, associate with MetS scores, in the middle-age group (r = 0.26, p = 0.006). Age-adjusted PAI1 was also significantly different between the MetS and control groups, and further associated with MetS scores (r = 0.31, P < 0.001), in the middle age group. CONCLUSION: DNAm GrimAge is a surrogate marker for MetS, and its component score, in Koreans. This association can be observed only in middle age. Therefore, appropriate DNA methylation clocks may aid in the prediction of Korean metabolic diseases.

Differential Gene Expression Changes in Human Primary Dental Pulp Cells Treated with Biodentine and TheraCal LC Compared to MTA.

This study aimed to analyze the effects of pulp capping materials on gene expression changes in primary tooth-derived dental pulp cells using next-generation sequencing. Dental pulp cells were extracted and treated with mineral trioxide aggregate (MTA), Biodentine (BD), or TheraCal LC (TC). Cell viability assays were performed. Total RNA was extracted and analyzed through mRNA sequencing. Bioinformatic analysis of differential gene expression in dental pulp cells exposed to BD or TC versus MTA was performed. MTA, BD, and TC exposure had no significant effect on pulp cell viability (p > 0.05). Gene sets associated with inflammatory response (p = 2.94 × 10-5) and tumor necrosis factor alpha (TNF-α) signaling via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway (p = 2.94 × 10-5) were enriched in all materials. In BD-treated cells, Wnt/ß-catenin signaling (p = 3.15 × 10-4) gene sets were enriched, whereas enrichment of interferon gamma (IFN-γ) response (p = 3 × 10-3) was observed in TC-treated cells. In gene plot analysis, marked increases in receptor activator of nuclear factor kappa-Β ligand (RANKL) expression were seen in TC-treated cells over time. Despite the similar cell viabilities exhibited among MTA-, BD-, and TC-treated cells, patterns of gene networks differed, suggesting that diverse functional gene differences may be associated with treatment using these materials.

Transcriptome Analysis of Deafness: Intracellular Signal Transduction Signaling Pathways Regulate Neuroplastic Changes in the Auditory Cortex.

HYPOTHESIS AND BACKGROUND: Hearing loss leads to synaptic changes in auditory neurons and their networks, and functions as a consequence of the interplay between genes and proteins. However, cellular and molecular mechanisms leading to deafness-induced plasticity in the auditory cortex (AC) remain unclear. Here, we examined the changes in gene expression and key signaling pathways that regulate differentially expressed genes (DEGs) in the AC following auditory deafferentation using RNA-sequencing (RNA-Seq) analysis. METHODS: Cochlear ablation-induced bilaterally deafened Sprague-Dawley rats were maintained for 12 weeks and their ACs were harvested. RNA-seq analysis was performed on each sample to identify which genes were expressed. This information was then used for comparative analysis of DEGs between samples. The statistical significance of DEGs was determined by fold change (|FC| > 1.5) and independent t test (p < 0.05). RESULTS: RNA-seq analysis identified 72 DEGs, of which 19 were upregulated and 53 were down-regulated after bilateral deafening in the ACs. Gene ontology (GO) analysis revealed the potential involvement of mitogen-activated protein kinase, tumor necrosis factor, and cyclic adenosine 3',5'-monophosphate (e.g., Bdnf, Gli1, and c-Fos) signaling pathways in regulating changes in the expression of the genes listed herein. The DEGs of interest-including c-Fos, Arc, Ntf3, and Gli1-from the RNA-seq analysis were consistent with result of quantitative reverse transcriptase polymerase chain reaction. CONCLUSION: RNA-seq analysis revealed that auditory deprivation in adult rats elicited changes in gene expression, transcription factor levels, and their complex interaction at specific gene promoters in the AC. Particularly, activation of intracellular signal transduction signaling pathways may be key to neuronal plasticity in deafness.

Nuclear receptor and VEGF pathways for gene-blood lead interactions, on bone mineral density, in Korean smokers.

Osteoporosis has a complex etiology and is considered a multifactorial polygenic disease, in which genetic determinants are modulated by hormonal, lifestyle, environmental, and nutritional factors. Therefore, investigating these multiple factors, and the interactions between them, might lead to a better understanding of osteoporosis pathogenesis, and possible therapeutic interventions. The objective of this study was to identify the relationship between three blood metals (Pb, Cd, and Al), in smoking and nonsmoking patients' sera, and prevalence of osteoporosis. In particular, we focused on gene-environment interactions of metal exposure, including a dataset obtained through genome-wide association study (GWAS). Subsequently, we conducted a pathway-based analysis, using a GWAS dataset, to elucidate how metal exposure influences susceptibility to osteoporosis. In this study, we evaluated blood metal exposures for estimating the prevalence of osteoporosis in 443 participants (aged 53.24 ± 8.29), from the Republic of Korea. Those analyses revealed a negative association between lead blood levels and bone mineral density in current smokers (p trend <0.01). By further using GWAS-based pathway analysis, we found nuclear receptor (FDR<0.05) and VEGF pathways (FDR<0.05) to be significantly upregulated by blood lead burden, with regard to the prevalence of osteoporosis, in current smokers. These findings suggest that the intracellular pathways of angiogenesis and nuclear hormonal signaling can modulate interactions between lead exposure and genetic variation, with regard to susceptibility to diminished bone mineral density. Our findings may provide new leads for understanding the mechanisms underlying the development of osteoporosis, including possible interventions.

Proteomic Biomarkers for Bisphenol A-Early Exposure and Women's Thyroid Cancer.

PURPOSE: For the target treatment and prevention of women's increased thyroid cancer, we focused on risks of environmental exposure to endocrine disrupting chemicals, particularly bisphenol A (BPA), and its high susceptible exposure-timing, particularly early exposure in lives. MATERIALS AND METHODS: Female ICR mice were exposed to BPA in utero and in early life (15, 75, and 300 mg/L of drinking water via pregnant mice and lactation). We identified BPA-responsive proteins in mice thyroid by two-dimensional gel electrophoresis, image analyses, and electrospray ionization quadrupole time-of-flight mass spectrometry. We further analyzed expression of the BPA-responsive proteins in women thyroid cancer patients (n=28). RESULTS: We found the altered 17 proteins in BPA dose-dependent manner among the thyroid tissues of offspring mice and identified nine proteins of them, including Anxa6, Atp5b, Hspa5, and Vcp, etc. In addition, we observed the positive association between blood BPA levels and mRNA expression of the ANXA6 and VCP not in normal but thyroid cancer tissues. CONCLUSION: Our study provides ANXA6 and VCP as proteomic biomarkers for BPA-early life exposure and their potential for women's thyroid cancer.

Shift of EMT gradient in 3D spheroid MSCs for activation of mesenchymal niche function.

Despite the wide use of mesenchymal stromal cells (MSCs) for paracrine support in clinical trials, their variable and heterogeneous supporting activity pose major challenges. While three-dimensional (3D) MSC cultures are emerging as alternative approaches, key changes in cellular characteristics during 3D-spheroid formation remain unclear. Here, we show that MSCs in 3D spheroids undergo further progression towards the epithelial-mesenchymal transition (EMT), driven by upregulation of EMT-promoting microRNAs and suppression of EMT-inhibitory miRNAs. The shift of EMT in MSCs is associated with widespread histone modifications mimicking the epigenetic reprogramming towards enhanced chromatin dynamics and stem cell-like properties, but without changes in their surface phenotype. Notably, these molecular shifts towards EMT in 3D MSCs caused enhanced stem cell niche activity, resulting in higher stimulation of hematopoietic progenitor self-renewal and cancer stem cell metastasis. Moreover, miRNA-mediated induction of EMT in 2D MSCs were sufficient to mimic the enhanced niche activity of 3D spheroid MSCs. Thus, the molecular hierarchy in the EMT gradient among phenotypically indistinguishable MSCs revealed the previously unrecognized functional parameters in MSCs, and the EMT-enhanced "naïve" mesenchymal state represents an 'activated mesenchymal niche' in 3D spheroid MSCs.

Heterogeneous Niche Activity of Ex-Vivo Expanded MSCs as Factor for Variable Outcomes in Hematopoietic Recovery.

Ex-vivo expanded mesenchymal stromal cells (MSCs) are increasingly used for paracrine support of hematopoietic stem cell (HSC) regeneration, but inconsistent outcomes have hindered ongoing clinical trials. Here, we show that significant heterogeneity in the niche activity of MSCs is created during their culture in various serum-supplemented media. The MSCs cultured under stimulatory or non-stimulatory culture conditions exhibited differences in colony forming unit-fibroblast contents, expression levels of cross-talk molecules (Jagged-1 and CXCL-12) and their support for HSC self-renewal. Accordingly, the enhancing effects of MSCs on hematopoietic engraftment were only visible when HSCs were co-transplanted with MSCs under stimulatory conditions. Of note, these differences in MSCs and their effects on HSCs were readily reversed by switching the cultures, indicating that the difference in niche activity can be caused by distinct functional state, rather than by clonal heterogeneity. Supporting the findings, transcriptomic analysis showed distinct upstream signaling pathways such as inhibition of P53 and activation of ER-stress response gene ATF4 for MSCs under stimulatory conditions. Taken together, our study shows that the niche activity of MSCs can vary rapidly by the extrinsic cues during culture causing variable outcomes in hematopoietic recoveries, and point to the possibility that MSCs can be pre-screened for more predictable efficacy in various cell therapy trials.

To quit or not: Vulnerability of women to smoking tobacco.

Tobacco smoking is currently on the rise among women, and can pose a greater health risk. In order to understand the nature of the increase in smoking prevalence among women, we focused on the vulnerability of women to smoking behaviors--smoking cessation or tobacco addiction--and performed a systematic review of the socioeconomic and intrinsic factors as well as tobacco ingredients that affect women's susceptibility to smoking tobacco. We observed that nicotine and other tobacco components including cocoa-relatives, licorice products, and menthol aggravate tobacco addiction in women rather than in men. Various genetic and epigenetic alterations in dopamine pathway and the pharmaco-kinetics and -dynamic factors of nicotine also showed potential evidences for high susceptibility to tobacco addiction in women. Therefore, we suggest systemic approaches to prevent tobacco smoking-related health risks, considering gene-environment-gender interaction.

A current review for biological monitoring of manganese with exposure, susceptibility, and response biomarkers.

People can be easily exposed to manganese (Mn), the twelfth most abundant element, through various exposure routes. However, overexposure to Mn causes manganism, a motor syndrome similar to Parkinson disease, via interference of the several neurotransmitter systems, particularly the dopaminergic system in areas. At cellular levels, Mn preferentially accumulates in mitochondria and increases the generation of reactive oxygen species, which changes expression and activity of manganoproteins. Many studies have provided invaluable insights into the causes, effects, and mechanisms of the Mn-induced neurotoxicity. To regulate Mn exposure, many countries have performed biological monitoring of Mn with three major biomarkers: exposure, susceptibility, and response biomarkers. In this study, we review current statuses of Mn exposure via various exposure routes including food, high susceptible population, effects of genetic polymorphisms of metabolic enzymes or transporters (CYP2D6, PARK9, SLC30A10, etc.), alterations of the Mn-responsive proteins (i.e., glutamine synthetase, Mn-SOD, metallothioneins, and divalent metal trnsporter1), and epigenetic changes due to the Mn exposure. To minimize the effects of Mn exposure, further biological monitoring of Mn should be done with more sensitive and selective biomarkers.

Molecular integration of HoxB4 and STAT3 for self-renewal of hematopoietic stem cells: a model of molecular convergence for stemness.

The upregulation of HoxB4 promotes self-renewal of hematopoietic stem cells (HSCs) without overriding the normal stem cell pool size. A similar enhancement of HSC self-renewal occurs when signal transducer and activator of transcription 3 (STAT3) is activated in HSCs. In this study, to gain insight into the functional organization of individual transcription factors (TFs) that have similar effects on HSCs, we investigated the molecular interplay between HoxB4 and STAT3 in the regulation of HSC self-renewal. We found that while STAT3-C or HoxB4 similarly enhanced the in vitro self-renewal and in vivo repopulating activities of HSCs, simultaneous transduction of both TFs did not have additive effects, indicating their functional redundancy in HSCs. In addition, activation of STAT3 did not cause changes in the expression levels of HoxB4. In contrast, the inhibition of STAT3 activity in HoxB4-overexpressing hematopoietic cells significantly abrogated the enhancing effects of HoxB4, and the upregulation of HoxB4 caused a ligand-independent Tyr-phosphorylation of STAT3. Microarray analysis revealed a significant overlap of the transcriptomes regulated by STAT3 and HoxB4 in undifferentiated hematopoietic cells. Moreover, a gene set enrichment analysis showed significant overlap in the candidate TFs that can recapitulate the transcriptional changes induced by HoxB4 or STAT3. Interestingly, among these common TFs were the pluripotency-related genes Oct-4 and Nanog. These results indicate that tissue-specific TFs regulating HSC self-renewal are functionally organized to play an equivalent role in transcription and provide insights into the functional convergence of multiple entries of TFs toward a conserved transcription program for the stem cell state.

The epigenome and cancer prevention: A complex story of dietary supplementation.

Epigenetic changes have been implicated in virtually all types of human malignancies. In contrast to genetic changes, epigenetic changes occur in a gradual manner during the tumorigenic process and they are potentially reversible. Because epigenetic changes have frequently been detected in high-risk populations, they are attractive targets to prevent the initiation of premalignant lesions or their advance to a malignant stage. A wide range of chemical entities has been found capable of altering the epigenome in animal models and humans. Epidemiological and laboratory-based studies suggested that these agents may have an anti-neoplastic effect against different cancer types. Several of these agents have been tested as dietary supplements, often with conflicting results. In this review, we discuss recent developments in our understanding of agents capable of modulating the epigenome and their potential to prevent human cancer when administered as dietary supplements.

Modulation of DNA methylation states and infant immune system by dietary supplementation with ω-3 PUFA during pregnancy in an intervention study.

BACKGROUND: Early-life exposures to tobacco smoke and some dietary factors have been identified to induce epigenetic changes in genes involved in allergy and asthma development. Omega-3 (n-3) polyunsaturated fatty acid (PUFA) intake during pregnancy could modulate key cytokines and T helper (Th) cell maturation; however, little is known about the mechanism by which ω-3 PUFA could have a beneficial effect in preventing inflammatory disorders. OBJECTIVE: We sought to test whether prenatal dietary supplementation with ω-3 PUFA during pregnancy may modulate epigenetic states in the infant immune system. DESIGN: This study was based on a randomized intervention trial conducted in Mexican pregnant women supplemented daily with 400 mg docosahexaenoic acid (DHA) or a placebo from 18 to 22 wk of gestation to parturition. We applied quantitative profiling of DNA methylation states in Th1, Th2, Th17, and regulatory T-relevant genes as well as LINE1 repetitive elements of cord blood mononuclear cells (n = 261). RESULTS: No significant difference in promoter methylation levels was shown between ω-3 PUFA-supplemented and control groups for the genes analyzed; however, ω-3 PUFA supplementation was associated with changes in methylation levels in LINE1 repetitive elements (P = 0.03) in infants of mothers who smoked during pregnancy. Furthermore, an association between the promoter methylation levels of IFNγ and IL13 was modulated by ω-3 PUFA supplementation (P = 0.06). CONCLUSIONS: Our results indicate that maternal supplementation with ω-3 PUFA during pregnancy may modulate global methylation levels and the Th1/Th2 balance in infants. Therefore, the epigenetic mechanisms could provide attractive targets for prenatal modulation and prevention of inflammatory disorders and potentially other related diseases in childhood and adulthood.

Dopamine increases Na+ absorption in the Reissner's membrane of the gerbil cochlea.

OBJECTIVE: The purpose of the present study was to investigate the effect of dopamine as a possible regulator of epithelial Na(+) channel (ENaC) in the Reissner's membrane (RM). METHODS: RM was freshly dissected from the gerbil cochlea, and short-circuit current (Isc) was measured using the voltage-sensitive vibrating probe technique. The dopamine receptor expression was examined using immunohistochemistry. RESULTS: The results showed that dopamine induced activation of the amiloride-sensitive Isc, but not after pre-treatment with amiloride. The D1-like receptor antagonist SCH-23390, but not the D2-like receptor antagonist sulpiride, decreased the stimulatory effect of dopamine on RM. The effect of dopamine on Na(+) transport via ENaC was still observed after blockade of the Na(+)-K(+)-ATPase by ouabain. D1 receptor immunoreactivity was observed in RM, stria vascularis and spiral ganglion. CONCLUSION: Na(+) transport in RM is activated by dopamine possibly via D1-like receptors, and intracellular mechanisms other than cAMP-mediated pathway may be involved.

Nutritional status of patients treated with radiotherapy as determined by subjective global assessment.

PURPOSE: The purpose of this prospective multi-institutional study was to evaluate the nutritional status of patients undergoing radiotherapy (RT) for treatment of head and neck, lung, or gastrointestinal cancer. MATERIALS AND METHODS: A total of 1,000 patients were enrolled in this study at seven different hospitals in Seoul, Korea between October 2009 and May 2010. The nutritional status of patients after receiving 3 weeks of RT was evaluated using subjective global assessment (SGA). The nutritional status of each patient was rated as well nourished (A), moderately malnourished (B), or severely malnourished (C). RESULTS: The mean age of patients in this study was 59.4 ± 11.9 years, and the male to female ratio was 7:3. According to the SGA results, 60.8%, 34.5%, and 4.7% of patients were classified as A, B, or C, respectively. The following criteria were significantly associated with malnutrition (SGA B or C; p < 0.001): loss of subcutaneous fat or muscle wasting (odds ratio [OR], 11.473); increased metabolic demand/stress (OR, 8.688); ankle, sacral edema, or ascites (OR, 3.234); and weight loss ≥5% (OR, 2.299). CONCLUSION: SGA was applied successfully to assess the nutritional status of most patients. The prevalence of malnutrition in a radiation oncology department was 39.2%. The results of this study serve as a basis for implementation of nutrition intervention to patients being treated at radiation oncology departments.

Set, a putative oncogene, as a biomarker for prenatal exposure to bisphenol A.

BACKGROUND: Bisphenol A (BPA), an endocrine disrupting chemical, has been suspected to pose carcinogenic risks. However, likely mechanisms are obscure and there are difficulties to estimating its real significance for cancer development. METHODS: We therefore studied BPA-induced proteomic alterations in immune organs of ICR mice offspring that were prenatally exposed to BPA (15 and 300 mg/L of drinking water). We performed 2D-gel analyses of samples, considering differences in spleen, exposure levels, sex, and ages. RESULTS: From proteomic analyses, we found various proteins were up- or down-regulated by BPA. Among them, SET, a putative oncogene and inhibitor of phosphatase 2A, was significantly down- regulated in a BPA dose-dependent manner. We also confirmed down-regulation of SET in western blot and real time PCR analyses. From gene network analysis, SET is predicted to communicate with other genes including CYP17, which is involved in biosynthesis and metabolism of sex-hormones. CONCLUSIONS: This study provided evidence that SET can be applied as a new biomarker for prenatal BPA exposure and suggests a potential new mechanism of action in that BPA may disrupt CYP17 via SET.

[The safety of early enteral feeding after emergency gastrointestinal surgery].

BACKGROUND/AIMS: Postoperative early feeding has many advantages, and current guidelines recommend the early diet or enteral feeding after gastrointestinal surgery. However, there are controversies in emergency situation. The aim of this study was to assess the safety of early enteral feeding in patients underwent emergency gastrointestinal (GI) surgery. METHODS: We reviewed the patients underwent emergency GI surgery by single surgeon from March 2008 to December 2010, retrospectively. The early feeding was defined when feeding was started within 72 hours after operation. RESULTS: Fifty-three patients were enrolled. Men were 31, with mean 60.6 (±18.5) years old age. Thirty-three patients were treated in the intensive-care unit after operation. The most common cause of operation was bowel perforation, and followed by intestinal obstruction. Segmental resection with primary anastomosis of small bowel is the most common operation. Thirty-two of them started the diet within 48 hours postoperatively. Twenty-nine patients had post-operative complications. Wound complications were the most common, and followed by the abdominal pain, and ileus. Wound complications were developed in 18 patients, and the post-feeding abdominal pain was in 7 patients. Anastomotic leakage and intraabdominal abscess were developed in 2 patients, and 1 patient required reoperation to treat the anastomotic disruption. One patient developed pneumonia and sepsis, and resolved under conservative treatment. There was no mortality in these patients. CONCLUSIONS: Early enteral feeding may be safe in cases of emergency GI surgery. However, it may require further studies to confirm the safety and feasibility of the early feeding in emergency situations.

Chemopreventive Effects of Korean Red Ginseng (Panax ginseng Meyer) on Exposure to Polycyclic Aromatic Hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs) are well known environmental carcinogens. PAH metabolites, especially BaP-7,8- dihydrodiol, 9,10 epoxide, initiate carcinogenesis via high specificity binding to DNA to form DNA adducts. The Korean red ginseng (KRG) from Panax ginseng has been suggested to protect against damages due to PAH exposure but the mechanism is unknown. Therefore, we investigated effects of KRG on PAH exposure using toxicokinetic methods and changes of PAH-induced oxidative damage during a 2 week-clinical trial (n=21 healthy young female, 23.71±2.43 years). To analyze antioxidative effects of KRG, we measured changes in the levels of urinary malondialdehyde (MDA) before and after KRG treatment. We observed a significant positive association between levels of urinary MDA and 1-hydroxypyrene, a biomarker of PAH exposures (slope=1.47, p=0.03) and confirmed oxidative stress induced by PAH exposures. A reverse significant correlation between KRG treatment and level of urinary MDA was observed (p=0.03). In summary, results of our clinical trial study suggest that KRG plays a significant role in antioxidative as well as toxicokinetic pathways against PAHs exposure.

P2Y4-mediated regulation of Na+ absorption in the Reissner's membrane of the cochlea.

The epithelial cells of Reissner's membrane (RM) are capable of transporting Na(+) out of endolymph via epithelial Na(+) channel (ENaC). However, much remains to be known as to mechanism of regulation of Na(+) absorption in RM. We investigated P2Y signaling as a possible regulatory mechanism of ENaC in gerbil RM using voltage-sensitive vibrating probe technique and immunohistochemistry. Results showed that UTP induced partial inhibition of the amiloride-sensitive short-circuit current but did not change short-circuit current when applied in the presence of amiloride. The inhibitory effect of UTP was not completely reversible in minutes. The response to UTP was inhibited by reactive blue-2 and 2',3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate but not by suramin or pyridoxalphosphate-6-azophenyl-2', 4'-disulfonic acid, which indicates this P2Y receptor as the P2Y(4) subtype. The phospholipase C (PLC) inhibitors 1-[6[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione and 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine markedly inhibited the effect of UTP on ENaC. In contrast, neither modulation of protein kinase C nor application of 2-aminoehoxydiphenyl borate affected P2Y(4)-mediated inhibition of ENaC. Immunoreactive staining for P2Y(4) was observed in the RM, apical membrane of stria vascularis, spiral ligament, and organ of Corti, including outer hair cell, inner hair cell, outer pillar cell, Deiters' cell, and Hensen cell. These results suggest that the physiological role of P2Y(4) receptor in RM is likely to regulate Na(+) homeostasis in the endolymph. The acute inhibition of ENaC activity by activation of P2Y(4) receptor is possibly mediated by decrease of phosphatidylinositol 4,5-biphosphate in the plasma membrane through PLC activation.

Applications of CYP-450 expression for biomonitoring in environmental health.

Cytochrome P450s (CYPs) are one of the first steps in the metabolism of xenobiotics, such as polycyclic aromatic hydrocarbons (PAHs), which are bioactivated into carcinogens. As such, changes in CYP expression are potential biomarkers in human biomonitoring applications. For the proper biomonitoring of environmental toxicants, it is important to understand the biological relevance of each biomarker and the associations among the biomarkers for uses as exposure, effects, and susceptibility biomarkers. Here, we have reviewed various aspects of CYPs for biomonitoring environmental health in terms of the CYP substrates, such as PAHs, aromatic amines, benzene/toluene, and tobacco smoking-related nitrosamines. This review also includes association studies between CYP phenotypical alterations and other exposure, susceptibility, and effect biomarkers. The association studies were mainly performed in CYP gene-transfected cells and noninvasive human biospecies, such as urine and peripheral blood. In conclusion, we suggest that phenotypical alterations in CYPs with exposure to environmental toxicants are useful as susceptibility or effect biomarkers, particularly when the phenotype-related genotypes are unknown.

Endocrine disrupting chemicals: human exposure and health risks.

Endocrine disrupting chemicals (EDCs) have been emphasized due to their threats in fertility, intelligence, and survival. For the last decade, many researchers have investigated EDC-health outcome. However, EDC responses in human were not clearly clarified through experimental and epidemiological data. Therefore, considering particular status of EDC endpoints, we suggest that one of the best ways to prevent unknown health risks from EDCs is to perform exposure monitoring or to do surveillance for EDC release into the environment. For this purpose, this review considers exposure status of EDCs, and EDC-related health risks, focusing on the mainly highlighted EDCs, such as dioxins/PCBs, DDT/DDE, bisphenol A, phthalates, alkylphenols, and phytoestrogens. We also reviewed tobacco, a mixed source of EDC-related endocrine disorders.