Device modeling of two-steps oxygen anneal-based submicron InGaZnO back-end-of-line field-effect transistor enabling short-channel effects suppression.

Amorphous oxide semiconductor (AOS) field-effect transistors (FETs) have been integrated with complementary metal-oxide-semiconductor (CMOS) circuitry in the back end of line (BEOL) CMOS process; they are promising devices creating new and various functionalities. Therefore, it is urgent to understand the physics determining their scalability and establish a physics-based model for a robust device design of AOS BEOL FETs. However, the advantage emphasized to date has been mainly an ultralow leakage current of these devices. A device modeling that comprehensively optimizes the threshold voltage (VT), the short-channel effect (SCE), the subthreshold swing (SS), and the field-effect mobility (µFE) of short-channel AOS FETs has been rarely reported. In this study, the device modeling of two-steps oxygen anneal-based submicron indium-gallium-zinc-oxide (IGZO) BEOL FET enabling short-channel effects suppression is proposed and experimentally demonstrated. Both the process parameters determining the SCE and the device physics related to the SCE are elucidated through our modeling and a technology computer-aided design (TCAD) simulation. In addition, the procedure of extracting the model parameters is concretely supplied. Noticeably, the proposed device model and simulation framework reproduce all of the measured current-voltage (I-V), VT roll-off, and drain-induced barrier lowering (DIBL) characteristics according to the changes in the oxygen (O) partial pressure during the deposition of IGZO film, device structure, and channel length. Moreover, the results of an analysis based on the proposed model and the extracted parameters indicate that the SCE of submicron AOS FETs is effectively suppressed when the locally high oxygen-concentration region is used. Applying the two-step oxygen annealing to the double-gate (DG) FET can form this region, the beneficial effect of which is also proven through experimental results; the immunity to SCE is improved as the O-content controlled according to the partial O pressure during oxygen annealing increases. Furthermore, it is found that the essential factors in the device optimization are the subgap density of states (DOS), the oxygen content-dependent diffusion length of either the oxygen vacancy (VO) or O, and the separation between the top-gate edge and the source-drain contact hole. Our modeling and simulation results make it feasible to comprehensively optimize the device characteristic parameters, such as VT, SCE, SS, and µFE, of the submicron AOS BEOL FETs by independently controlling the lateral profile of the concentrations of VO and O in two-step oxygen anneal process.

Antiobesity and Hepatoprotective Effects of Protein Hydrolysates Derived from Protaetia brevitarsis in an Obese Mouse Model.

Background: Obesity induced by excessive nutrients can cause fatty liver and metabolic dysfunction, which leads to hepatic dysfunction and local/systemic inflammatory responses. Previously, we analyzed the antioxidant, antilipotoxicity, and anti-inflammatory effects of protein hydrolysates in vitro. The aim of the present study is to investigate the antiobesity and hepatoprotective effects of protein hydrolysates derived from Protaectia brevitas (PHPB) in an obese mouse model. Methods: For this in vivo study, 40 mice were included and divided into four groups: (1) normal diet group, (2) high-fat-diet (ctrl(-)) group, (3) high-fat-diet and silymarin-treated (ctrl(+)) group, and (4) high-fat-diet and PHPB-treated group. After 6 weeks of treatment, body weight and the amount of daily food intake were observed. Moreover, the major organs and blood of animals were collected for the analysis of serum chemistry, histopathological examination, and obesity- and inflammation-related gene expressions. Results: The body weight and the amount of daily food intake significantly decreased in the PHPB-treated group compared with those in the ctrl(-) group. The levels of serum ALT, AST, ALP, creatinine, blood urea nitrogen, glucose, bilirubin, total cholesterol, TG, low-density lipoprotein, IL-6, TNF-α, and IGF-1 significantly reduced in the PHPB-treated group, whereas the serum free fatty acid, albumin, high-density lipoprotein, and adiponectin concentrations increased. In the analysis of weight of the liver, kidney, lungs, spleen, and fat tissues (from epididymal, perirenal, and mesentery tissues), the PHPB-treated group showed decreased values compared with the ctrl(-) group. In the histopathological analysis, the PHPB-treated group showed significantly reduced macrovesicular fatty change and inflammatory cell infiltration in the liver, and the size of the adipocyte in the epididymis also significantly decreased. The obesity- and inflammation-related gene (IL-6, TNF-α, IGF-1, leptin, AP2/FABP4, AMPK-α2, ß3AR, and PPAR-γ) expressions in the liver and epididymal adipose tissue were reduced in the PHPB-treated group. Conclusions: Overall, the results of this study suggest that the protein hydrolysates that derived from Protaectia brevitas produce antiobesity and hepatoprotective effects via anti-inflammatory activities.

Transcriptome analysis upon potassium usnate exposure reveals ATF3-induced apoptosis in human gastric and colon cancer cells.

BACKGROUND: Potassium usnate (KU), a water-soluble form of usnic acid, shows anticancer activity. However, the underlying mechanisms have not been fully elucidated. PURPOSE: We aimed to identify the pathways involved in anticancer effects of KU in human gastric cancer (GC) and colorectal cancer (CRC) cells using RNA-sequencing (RNA-seq) based transcriptome analysis. STUDY DESIGN: We analyzed the cytotoxic effects of KU to identify the common molecular events in GC and CRC cells upon KU exposure using unbiased approaches. METHODS: Cell viability assays and western blot experiments were used to examine apoptotic changes, cell cycle arrest, and endoplasmic reticulum (ER) stress-induced cellular responses in KU-treated cells. Total RNA from KU-treated human GC and CRC cells was prepared for RNA-seq analysis. Gene ontology term and gene set enrichment analyses were used to identify the key mediators of the cytotoxic effects of KU. The expression of ER stress-induced apoptotic markers was evaluated using quantitative reverse-transcription PCR and western blot analysis. Chromatin immunoprecipitation assays for ATF3 and H3K27ac, and ATF3 knockdown were employed to verify the underlying molecular mechanisms. The inhibitory effect of KU on tumor growth in vivo was validated with metastatic tumor nodule formations in a mouse liver model. RESULTS: KU exerted cytotoxicity in human GC and CRC cells through the activation of the ER stress-induced apoptotic pathway. KU stimulated ATF3 expression, an important mediator of molecular events of apoptosis. ATF3 binds to the promoter region of ATF3, CHOP, GADD34, GADD45A, DR5, and PUMA genes and subsequently promoted apoptotic events. Knockdown of ATF3 significantly reduced the expression of ATF3 target genes and the cytotoxic effects of KU. The intraperitoneal injection of KU induced ATF3 and the apoptosis of implanted colon cancer cells, resulting in reduced metastatic tumor growth in the mouse livers. CONCLUSION: KU exerts cytotoxic effects in human GC and CRC cells by triggering ER stress-induced apoptosis via an ATF3 dependent pathway.

Renal Protective Effect of Beluga Lentil Pretreatment for Ischemia-Reperfusion Injury.

MATERIALS AND METHODS: Mice were divided into four groups: normal, untreated, low- (2 mg), and high-dose (8 mg) beluga lentil treatment groups. Beluga lentil was orally administered for 2 weeks, followed by bilateral renal ischemia for 20 min and reperfusion for 30 min. Blood samples and kidney tissues were collected and analyzed to investigate renal function, histopathology, epithelial and endothelial cell damage, apoptosis, oxidative stress, and inflammatory responses. RESULTS: The pretreated groups maintained renal function, with significantly lower blood urea nitrogen (BUN) and creatinine levels, compared with the other groups. The histopathological analysis showed reduced proximal tubule injury and decreased injury-related molecule (kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)) secretion in the pretreated groups compared with the other groups. Terminal deoxynucleotidyl transferase dUTP nick-end labeling- (TUNEL-) positive cells and the secretion of apoptosis-related molecules (Fas and caspase 3) were significantly reduced in the pretreated groups compared with the other groups. The pretreated groups showed positive microvessel-associated gene (cluster of differentiation (CD31)) expression and negative adhesion molecule (intracellular adhesion molecule 1 (ICAM-1)) expression. An antioxidant effect was observed in the pretreatment groups, with reduced malonaldehyde (MDA) expression and increased antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx)) secretion. In the pretreated groups, F4/80+ macrophages and CD4+ T cell infiltration were inhibited and proinflammatory cytokine (interleukin- (IL-) 1ß, IL-6, and tumor necrosis factor- (TNF-) α) levels decreased; however, the levels of anti-inflammatory cytokines (transforming growth factor- (TGF-) ß, IL-10, and IL-22) increased. CONCLUSIONS: Beluga lentil pretreatment demonstrated protective effects against I/R-induced renal damage, via antiapoptotic, anti-inflammatory, and antioxidant activities.

In Vitro and In Vivo Protective Effects of Lentil (Lens culinaris) Extract against Oxidative Stress-Induced Hepatotoxicity.

Excessive oxidative stress plays a role in hepatotoxicity and the pathogenesis of hepatic diseases. In our previous study, the phenolic extract of beluga lentil (BLE) showed the most potent in vitro antioxidant activity among extracts of four common varieties of lentils; thus, we hypothesized that BLE might protect liver cells against oxidative stress-induced cytotoxicity. BLE was evaluated for its protective effects against oxidative stress-induced hepatotoxicity in AML12 mouse hepatocytes and BALB/c mice. H2O2 treatment caused a marked decrease in cell viability; however, pretreatment with BLE (25-100 µg/mL) for 24 h significantly preserved the viability of H2O2-treated cells up to about 50% at 100 µg/mL. As expected, BLE dramatically reduced intracellular reactive oxygen species (ROS) levels in a dose-dependent manner in H2O2-treated cells. Further mechanistic studies demonstrated that BLE reduced cellular ROS levels, partly by increasing expression of antioxidant genes. Furthermore, pretreatment with BLE (400 mg/kg) for 2 weeks significantly reduced serum levels of alanine transaminase and triglyceride by about 49% and 40%, respectively, and increased the expression and activity of glutathione peroxidase in CCl4-treated BALB/c mice. These results suggest that BLE protects liver cells against oxidative stress, partly by inducing cellular antioxidant system; thus, it represents a potential source of nutraceuticals with hepatoprotective effects.

Efficacy of combination therapy with pentosan polysulfate sodium and adipose tissue-derived stem cells for the management of interstitial cystitis in a rat model.

We evaluated the synergistic effects of pentosan polysulfate sodium (PPS) and mesenchymal stem cells (MSCs) in an interstitial cystitis (IC) rat model. After generation of the IC rat model, the rats were divided into 4 groups according to the treatment they received: phosphate-buffered saline injection into bladder submucosa, daily oral PPS feeding, MSC injection into bladder submucosa, or MSC injection into bladder submucosa with daily oral PPS feeding. After treatment, conscious cystometry and pain scale measurement were performed and their bladders were obtained for histological and proinflammatory-related gene expression analysis. On cystometric analysis, all treatment groups showed significantly increased intercontraction intervals and lower pain scores compared to those of the control group. Histological analysis revealed regenerated urothelium, less fibrosis, and decreased mast cell infiltration in all treatment groups compared to the control group. Significantly lower expression of TNF-α, IFN-γ, MCP, IL-6, TLR2, and TLR11 was observed in the PPS with MSC group compared to the other groups. Combination therapy with PPS and MSCs showed histological and functional effects in an IC rat model, including synergistic effects leading to increased intercontraction interval and decreased inflammatory reactions.

Ultrasensitive Electrical Detection of Hemagglutinin for Point-of-Care Detection of Influenza Virus Based on a CMP-NANA Probe and Top-Down Processed Silicon Nanowire Field-Effect Transistors.

Rather than the internal genome nucleic acids, the biomolecules on the surface of the influenza virus itself should be detected for a more exact and rapid point-of-care yes/no decision for influenza virus-induced infectious diseases. This work demonstrates the ultrasensitive electrical detection of the HA1 domain of hemagglutinin (HA), a representative viral surface protein of the influenza virus, using the top-down complementary metal oxide semiconductor (CMOS) processed silicon nanowire (SiNW) field-effect transistor (FET) configuration. Cytidine-5'-monophospho-N-acetylneuraminic acid (CMP-NANA) was employed as a probe that specifically binds both to the aldehyde self-aligned monolayer on the SiNWs and to HA1 simultaneously. CMP-NANA was serially combined with two kinds of linkers, namely 3-aminopropyltriethoxysilane and glutaraldehyde. The surface functionalization used was verified using the purification of glutathione S-transferase-tagged HA1, contact angle measurement, enzyme-linked immunosorbent assay test, and isoelectric focusing analysis. The proposed functionalized SiNW FET showed high sensitivities of the threshold voltage shift (ΔVT) ~51 mV/pH and the ΔVT = 112 mV (63 mV/decade) with an ultralow detectable range of 1 fM of target protein HA1.

Fabrication of Gradient Nanopattern by Thermal Nanoimprinting Technique and Screening of the Response of Human Endothelial Colony-forming Cells.

Nanotopography can be found in various extracellular matrices (ECMs) around the body and is known to have important regulatory actions upon cellular reactions. However, it is difficult to determine the relation between the size of a nanostructure and the responses of cells owing to the lack of proper screening tools. Here, we show the development of reproducible and cost-effective gradient nanopattern plates for the manipulation of cellular responses. Using anodic aluminum oxide (AAO) as a master mold, gradient nanopattern plates with nanopillars of increasing diameter ranges [120-200 nm (GP 120/200), 200-280 nm (GP 200/280), and 280-360 nm (GP 280/360)] were fabricated by a thermal imprinting technique. These gradient nanopattern plates were designed to mimic the various sizes of nanotopography in the ECM and were used to screen the responses of human endothelial colony-forming cells (hECFCs). In this protocol, we describe the step-by-step procedure of fabricating gradient nanopattern plates for cell engineering, techniques of cultivating hECFCs from human peripheral blood, and culturing hECFCs on nanopattern plates.

Perception of and attitude toward ethical issues among Korean occupational physicians.

BACKGROUND: Occupational physicians (OPs) have complex relationships with employees, employers, and the general public. OPs may have simultaneous obligations towards third parties, which can lead to variable conflicts of interests. Among the various studies of ethical issues related to OPs, few have focused on the Korean OPs. The aim of the present survey was to investigate the ethical contexts, the practical resolutions, and the ethical principles for the Korean OPs. METHODS: An email with a self-administered questionnaire was sent to members of the Korean Society of Occupational and Environmental Medicine, comprising 150 specialists and 130 residents. The questionnaire was also distributed to 52 specialists and 46 residents who attended the annual meeting of the Korean Association of Occupational and Environmental Clinics in October 2015, and to 240 specialists by uploading the questionnaire to the online community 'oem-doctors' in February 2016. The responses to each question (perception of general ethical conflicts, recognition of various ethical codes for OPs, core professional values in ethics of occupational medicine, and a mock case study) were compared between specialists and residents by the chi-squared test and Fisher's exact test. RESULTS: Responses were received from 80 specialists and 71 residents. Most participants had experienced ethical conflicts at work and felt the need for systematic education and training. OPs suffered the most ethical conflicts in decisions regarding occupational health examination and evaluation for work relatedness. Over 60% of total participants were unaware of the ethical codes of other countries. Participants thought 'consideration of worker's health and safety' (26.0%) and 'neutrality' (24.7%) as the prominent ethical values in professionality ofoccupational medicine. In mock cases, participants chose beneficence and justice for fitness for work and confidential information acquired while on duty, and beneficence and respect for autonomy in pre-placement examinations. CONCLUSIONS: This study evaluated the current perception of and attitude toward ethical issues among the Korean OPs. These findings will facilitate the development of a code of ethics and the ethical decision-making program forthe Korean OPs.

Effect of Paeotang on tumor necrosis factor α-induced vascular inflammation in human umbilical vein endothelial cells.

OBJECTIVE: To investigate whether Paeotang (10-50 µg/mL) suppresses tumor necrosis factor α (TNF-α)-induced vascular inflammatory processes in human umbilical vein endothelial cells (HUVEC). METHODS: The ingredients composed of Paeotang include Glycyrrhiza glabra, Zingiber officinale, Cinnamomum zeylanuicum, Salvia miltiorrhiza, Prunus persica, Paeonia szechuanica, Poria cocos and Cynanchum wilfordii. Herbs were mixed according to equal ratio of weight and ground into a crude powder. The effect of Paeotang on the expression of cell adhesion molecules and protective role in HUVEC stimulated by TNF-α were evaluated. RESULTS: Pretreatment with Paeotang decreased TNF-α-induced adhesion of HL-60 monocytic cells, as well as protein and mRNA expressions of intracellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and endothelial-selectin (E-selectin). Paeotang also dose-dependently inhibited TNF-α-induced matrix metalloproteinase-2 and -9 expressions. Paeotang significantly decreased TNF-α-induced intracellular reactive oxygen species (ROS) production. The Western blot and immunofluorescence analysis showed that Paeotang suppressed the translocation of p65 nuclear factor κB (NF-κB) to the nucleus. In addition, Paeotang inhibited the TNF-α-induced degradation of NF-κB inhibitor α (IκB-α) and by inhibiting the phosphorylation of IκB-α. Furthermore, pretreatment of Paeotang increased the heme oxygenase 1 (HO-1) and nuclear factor erythroid-2-related factor 2 (Nrf2) protein expression in HUVECs stimulated TNF-α. HO-1 was inhibited by Sn-protoporphyrin, HO-1 inhibitor, and increased by cobalt protopophyrin, HO-1 inducer. Furthermore, HO-1 induction was increased by single processing of Paeotang in a dose-dependent manner. CONCLUSION: These data suggest that Paeotang might be a benefificial therapeutic in vascular inflflammation through regulation of Nrf2-mediated HO-1 expression and inhibition of ROS/NF-κB signaling pathway. Thus, Paeotang maybe serve as a potential anti-atherogenic agent.

Blood lead concentration and related factors in Korea from the 2008 National Survey for Environmental Pollutants in the Human Body.

This study evaluated blood lead concentrations in the Korean general population and the correlation between various exposure sources using data from the 2008 Korea National Survey for Environmental Pollutants in the Human Body (National Institute of Environmental Research, Korea). The general and occupational characteristics were gathered from 5136 participants who were 20 years of age and older using a structured questionnaire. Blood lead concentrations were analyzed using an atomic absorption spectrophotometer. Statistical analysis was performed using multiple linear regressions of the log lead concentrations to the independent variables such as age, gender, smoke, herbal medication and drug consumption, drinking water, and living area. Geometric mean (GM) blood lead concentrations in Korean adults were 19.7 µg/l. The blood lead concentrations increased with age; the highest concentrations were found in the 50-69-year age group (p<0.001). Males were higher than in females (p<0.001). Current smokers and drinkers had higher concentrations than nonsmokers (p<0.001) and nondrinkers (p<0.001), respectively. People who took herbal medication and drug consumption were higher than those who did not (p<0.001). Education level was negatively associated with blood lead concentration (p<0.001). People living in or around industrial areas had elevated blood lead concentration (p<0.001). Family income was also negatively associated with lead concentration, but not significantly. For drinking water, the underground water (spring or well water) drinking group had higher concentrations than other types of water drinking groups, but not significantly (p=0.063). The blood lead concentrations by occupation were significant (p<0.034): the highest was in laborer and Agricultural-Fishery-Forestry and the lowest in office workers. In women, blood lead concentrations tended to decrease with increasing delivery times, but not significantly. The blood lead concentration (GM) of the general adult population in Korea has decreased over time from 45.8 µg/l (1999) to 19.7 µg/l (2008). Although it is still higher than in other countries such as the United States and Canada, it is rapidly decreasing. Gender, age, smoking and alcohol drinking status, herbal medication and drug consumption, education level, living area and occupation were significantly related to the blood lead concentrations in Korea.

Control of energy balance by hypothalamic gene circuitry involving two nuclear receptors, neuron-derived orphan receptor 1 and glucocorticoid receptor.

Nuclear receptors (NRs) regulate diverse physiological processes, including the central nervous system control of energy balance. However, the molecular mechanisms for the central actions of NRs in energy balance remain relatively poorly defined. Here we report a hypothalamic gene network involving two NRs, neuron-derived orphan receptor 1 (NOR1) and glucocorticoid receptor (GR), which directs the regulated expression of orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in response to peripheral signals. Our results suggest that the anorexigenic signal leptin induces NOR1 expression likely via the transcription factor cyclic AMP response element-binding protein (CREB), while the orexigenic signal glucocorticoid mobilizes GR to inhibit NOR1 expression by antagonizing the action of CREB. Also, NOR1 suppresses glucocorticoid-dependent expression of AgRP and NPY. Consistently, relative to wild-type mice, NOR1-null mice showed significantly higher levels of AgRP and NPY and were less responsive to leptin in decreasing the expression of AgRP and NPY. These results identify mutual antagonism between NOR1 and GR to be a key rheostat for peripheral metabolic signals to centrally control energy balance.

Enhanced oral bioavailability of docetaxel in rats by four consecutive days of pre-treatment with curcumin.

As with many other anti-cancer agents, docetaxel is a substrate for ATP-binding cassette transporters such as P-glycoprotein and its metabolism is mainly catalysed by CYP3A. In order to improve the oral bioavailability of docetaxel, a component of turmeric, curcumin, which can down-regulate the intestinal P-glycoprotein and CYP3A protein levels, was used for the pre-treatment of rats before the oral administration of docetaxel. Curcumin (100 mg/kg) did not significantly modify the pharmacokinetics of docetaxel when given orally 30 min before the administration of docetaxel. However, the C(max) of docetaxel in rats pre-treated with curcumin for four consecutive days was significantly increased (p<0.01) by about 10 times compared to that of the docetaxel control, and the area under the plasma concentration-time curve (AUC) was about eight times higher than that of the control. Consequently, the absolute bioavailability of docetaxel in the treatment group (four days of curcumin at 100 mg/kg) was about 40%, which was a significant increase of about eightfold in comparison to the control value. Thus, the oral bioavailability of docetaxel was enhanced by the co-administration of regular curcumin. It could be possible to administer docetaxel orally, besides the established i.v. route.

Anti-angiogenic activity of methanol extract of Phellinus linteus and its fractions.

AIM OF THE STUDY: The aim of the present study was to investigate the effects of MeOH extract of PL (PLME) and its fractions on angiogenesis. MATERIALS AND METHODS: PLME and its subsequent fractions (methylene chloride, ethyl acetate, n-butanol and aqueous fractions) were evaluated in vitro. Specifically, the anti-angiogenic activities of PLME and its fractions were investigated by measuring their effects on the proliferation, migration, tube formation and phosphorylation of vascular endothelial growth factor receptor (VEGFR)-2 in human umbilical vein endothelial cells (HUVECs). In addition, the in vivo Matrigel plug model was applied to evaluate new vessel formation. RESULTS: The results revealed that PLME and its subsequent fractions, except for the aqueous fraction, led to significant inhibition of the proliferation, migration, tube formation and VEGFR-2 phosphorylation of HUVECs as well as in vivo angiogenesis. CONCLUSIONS: These findings indicate the potential for the use of PLME in pathological situations involving stimulated angiogenesis, such as inflammation and tumor development.

The anti-inflammatory effects of a methanolic extract from Radix Isatidis in murine macrophages and mice.

Radix Isatidis is the dried root of the plant Isatidis indigotica Fort (family Cruciferae) and traditionally used as an anti-viral, anti-bacterial, anti-endotoxic, and immune regulatory agent in the folk medicine of Korea and China. The aim of the present study was to determine the anti-inflammatory effects of methanolic extracts of Radix Isatidis (RIME) in lipopolysaccharide (LPS)-stimulated murine macrophages and in a TPA-induced ear edema animal model. Anti-inflammatory effects of RIME were examined in LPS-stimulated RAW 264.7 macrophages. In order to investigate the effects of RIME in vivo, activation of myeloperoxidase, and histological assessment were examined in the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced mouse ear edema model. RIME significantly inhibited the release from macrophages of inflammatory mediators such as nitric oxide, prostaglandin E(2), and pro-inflammatory cytokines. Topical administration of RIME at 1-5 mg/ear resulted in reduction of ear inflammation in mice. Thus, our results indicate that the anti-inflammatory effects of RIME involve decreased production of inflammatory mediators, which suggests that RIME may have therapeutic potential in a variety of inflammation-related diseases.

Effects of manganese exposure on dopamine and prolactin production in rat.

Although manganese (Mn) has been shown to increase prolactin (PRL) by decreasing dopamine (DA) in the hypothalamus, the mechanism of Mn-induced regulation of the hypothalamic-hypophyseal-pituitary axis is unclear. We assessed the effects of inhaled Mn on hypothalamic DA and pituitary PRL production and evaluated the role of pituitary-specific transacting factor 1 (Pit-1), a transacting factor of PRL gene, in Mn-induced changes in PRL secretion in the rat brain. Male rats exposed to Mn for 4 or 13 weeks (1.5 mg/m3, 6 h/day, 5 days/week) showed a progressive and significant decrease in hypothalamic DA, whereas PRL and Pit-1 mRNA levels increased in response to Mn exposure. These results suggest that exposure to Mn decreases hypothalamic DA and promotes the production of PRL in the pituitary and that Pit-1 might be a regulator of DA and PRL.

Effects of Chromium (VI) Exposure on the Placental Function and Reproduction in Rats.

OBJECTIVE: This study aimed to investigate the toxic effects of chromium (VI) on the placental function and reproduction in rats. For the study, the placental prolactin-growth hormone (PRL-GH) gene expression, placental trophoblast cell differentiation and reproductive data were analyzed. METHODS: The pregnancies of F344 Fisher rats were checked by the presence of a copulatory plug or sperm in the vaginal smear, which was defined as day 0 of the pregnancy. Pregnant rats were divided into the three groups. The control group was given tap water (chromium level < 0.001 ppm) and the remaining groups were given 250 or 750 ppm of chromium (VI) [as potassium dichromate], from day 7 to 19 of the pregnancy. Rats were sacrificed at days 11 and 20 of pregnancy. The mRNA levels of PRL-GH and Pit-1a and b isotype genes were analyzed by Northern blot hybridization and reverse transcriptionpolymerase chain reaction (RT-PCR). The hormonal concentration was analyzed by radioimmunoassay, and the differentiation of placental trophoblast cells were observed by histochemical studies. Reproductive data, such as placental and fetal weights, pregnancy period, and litter size, were surveyed at day 20 of pregnancy and after birth. A statistical analysis was carried out using the SAS program (version 8.1). RESULTS: The mRNA levels of the prolactin-growth hormone (PRL-GH) family of genes were dose dependently reduced by chromium exposure. The mRNA levels of Pit-1a and b isotype genes that induce the expression of the PRL-GH family of genes were also reduced by chromium exposure. The PRL-GH hormonal concentration in the rat placenta, fetus and maternal blood were decreased by chromium exposure. In the middle stage of pregnancy (day 11), a high dose of chromium suppressed the differentiation of spongiotrophoblast cells that secret the PRLGH hormones. In the last stage of pregnancy (day 20), a high dose of chromium induced apoptosis of placental cells. Reproductive data, such as placental and fetal weights, litter size, were reduced, but the pregnancy period was extended in the group exposed to chromium compared with the controls. CONCLUSIONS: Chromium (VI) disrupts the ordered functions of the placenta, which leads to reproductive disorders in rats.