Chae Kwan Lee

p-hydroxybenzyl alcohol prevents brain injury and behavioral impairment by activating Nrf2, PDI, and neurotrophic factor genes in a rat model of brain ischemia

The therapeutic goal in treating cerebral ischemia is to reduce the extent of brain injury and thus minimize neurological impairment. We examined the effects of p-hydroxybenzyl alcohol (HBA), an active component of Gastrodia elata Blume, on transient focal cerebral ischemia-induced brain injury with respect to the involvement of protein disulphide isomerase (PDI), nuclear factor-E2-related factor 2 (Nrf2), and neurotrophic factors. All animals were ovariectomized 14 days before ischemic injury. Ischemic injury was induced for 1 h by middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion. Three days before MCAO, the vehicle-treated and the HBA-treated groups received intramuscular sesame oil and HBA (25 mg/kg BW), respectively. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed decreased infarct volume in the ischemic lesion of HBA-treated animals. HBA pretreatment also promoted functional recovery, as measured by the modified neurological severity score (mNSS; p < 0.05). Moreover, expression of PDI, Nrf2, BDNF, GDNF, and MBP genes increased by HBA treatment. In vitro, H2O2-induced PC12 cell death was prevented by 24 h HBA treatment, but bacitracin, a PDI inhibitor, attenuated this cytoprotective effect in a dose-dependent manner. HBA treatment for 2 h also induced nuclear translocation of Nrf2, possibly activating the intracellular antioxidative system. These results suggest that HBA protects against brain damage by modulating cytoprotective genes, such as Nrf2 and PDI, and neurotrophic factors.

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.

Perfluorooctanoic acid-induced inhibition of placental prolactin-family hormone and fetal growth retardation in mice

Perfluorooctanoic acid (PFOA) is a persistent pollutant worldwide and even found in human cord blood and breast milk. Some animal studies have reported that PFOA causes developmental toxicity such as fetal weight loss, but the mechanism is still unclear. This study focused on developmental toxicity of PFOA, particularly impacts of PFOA on placental endocrine function such as placental prolactin (PRL)-family hormone gene expression and fetal growth in mouse. Time-mated CD-1 mice were dosed by gavage with 0, 2, 10 and 25 mg/kg B.W/day of PFOA (n-10) dissolved with de-ionized water from gestational day (GD) 11-16. During treatment, body weight of each pregnant mouse was measured daily. On day 16, caesarean sections were performed and developmental data were observed. Three placentas from three different pregnant mice were assigned to each of the following experiments. The mRNA levels of mouse placental lactogen (mPL)-II, prolactin like protein (mPLP)-E, -F and Pit-1α and β isotype mRNAs, a transacting factor of mPLs and mPLPs genes, were analyzed using northern blot, in situ hybridization and RT-PCR, respectively. Maternal body weight gain was significantly declined from GD 13 in the PFOA treated groups compared to control. Developmental data such as fetal and placental weights were significantly decreased in accordance with PFOA dosage. Number of dead fetuses and post-implantation losses were significantly increased in the PFOA-exposed groups. In addition, placental efficiency (fetal weight/placental weight) was significantly reduced in PFOA treated groups in accordance with PFOA dosage. Histopathologic changes were observed in placenta. Dose dependent necrotic changes were observed in both 10 mg and 25 mg PFOA treated groups. Cell frequency of glycogen trophoblast cell and parietal trophoblast giant cell were decreased dose dependently in the junctional zone. In the labyrinth zone, sinusoidal trophoblast giant cell frequency was decreased in the 25 mg PFOA treated group. Also, morphological change such as crushed nuclear (atrophy) of trophoblast cells was observed in 25 mg PFOA treated group. Finally, mRNA levels of the mPL-II, mPLP-E, -F and Pit-1α and β were significantly reduced in the PFOA treated groups dose dependently. In addition, the changing pattern between mPL-II, mPLP-E, -F mRNA levels and fetal body weight showed positive relationship. In conclusion, the inhibitory effects of PFOA on the placental prolactin-family hormone genes expression may be secondary effects to insufficient trophoblast cell type differentiation and/or increased trophoblast cell necrosis. The impacts of PFOA on placental development and endocrine function reduced the placental efficiency and partly contributed to the fetal growth retardation in the mouse.

Effects of cadmium on the expression of placental lactogens and Pit-1 genes in the rat placental trophoblast cells.

Cadmium is an endocrine disrupter (ED) with detrimental effects on mammalian reproduction. The placenta is a primary target for cadmium toxicity during pregnancy. Very little of this metal crosses the placenta to the fetus, and consequently it accumulates in high concentrations in the placenta. Cadmium affects on steroid synthesis and has estrogen- and androgen-like activities. In this study, we investigated the toxic effects of cadmium on placental trophoblast cells as well as the mRNA levels of placental lactogens (PLs), which are under the control of estrogen and play a pivotal role during pregnancy. Pregnant F344 Fisher rats were injected subcutaneously with 0, 0.2, and 2.0mg/kg BW/day of cadmium (CdCl(2)) dissolved in saline from days 11 to 19 of pregnancy and were sacrificed on day 20. The mRNA levels of the PL-Iv and -II genes and Pit-1alpha and beta isotype genes, the trans-acting factor of PLs, were analyzed by Northern blot hybridization and reverse transcription-polymerase chain reaction, respectively. The frequency of the placental trophoblast cells was observed histochemically. Developmental data and apoptotic chromosomal DNA fragmentation of placental cells were also observed. The mRNA levels of PL-Iv and -II were reduced in a dose-dependent manner by cadmium. The mRNA levels of the Pit-1alpha and beta isotype genes were also reduced by cadmium. In the uterus-conjugated region of the placental junctional zone, the frequency rates of trophoblast cells were lower in the cadmium-treated groups than in the control group. High-dose cadmium exposure (2.0mg) induced not only the reduction of trophoblast cell frequency but also apoptotic chromosomal DNA fragmentation in the junctional zone of the placenta. Developmental metrics such as placental and fetal weights and a number of live fetuses, decreased, while a numbers of resorptions, dead fetuses, and post-implantation losses increased significantly (p<0.05) in the cadmium-treated groups compared to the control. These data suggested that cadmium inhibits the expression of PL genes and reduces the number of trophoblast cells in the rat placenta via an estrogen-like activity, leading to significant toxic effects on placental growth and physiological function in rats.

Effects of perfluorooctane sulfuric acid on placental PRL-family hormone production and fetal growth retardation in mice.

Perfluorooctane sulfuric acid (PFOS) is a persistent organic pollutant, causes fetal growth retardation but the mechanism is still unclear. This study focused on PFOS-induced toxicity such as placental trophoblast cell histopathological changes, endocrine function (i.e., prolactin (PRL)-family hormone production) and subsequent fetal growth retardation in mice. Maternal body weight gain, placental and fetal weights were significantly decreased in proportion to PFOS dosage. Placental efficiency (fetal weight/placental weight) was significantly reduced dose-dependently. Necrotic changes were observed in PFOS-treated placental tissues, and the area of injury increased dose-dependently. Finally, mRNA levels and maternal serum concentrations of the PRL-family hormones (mPL-II, mPLP-Cα, mPLP-K) were significantly reduced dose-dependently. In addition, the changing pattern between PRL-family hormone concentrations and fetal body weight was positively correlated. These results suggest that gestational PFOS treatment induces placental histopathological changes and disruption of endocrine function, finally may lead to fetal growth retardation in mice.

Secondhand Smoke Exposure and Urine Cotinine Concentrations by Occupation among Korean Workers: Results from the 2008 Korea National Survey for Environmental Pollutants in the Human Body

This study aimed to estimate the status of secondhand smoke (SHS) exposure through urine cotinine analysis among nonsmoking workers in Korea and to analyze factors affecting urine cotinine concentrations. Data were based on “The 2008 Korea National Survey for Environmental Pollutants in the Human Body,” a cross-sectional study of the National Institute of Environmental Research of Korea. We selected 1448 nonsmoking adult workers from 200 localities to participate in this survey. Urine cotinine concentrations were analyzed using a gas chromatograph-mass selective detector. We calculated separate covariate-adjusted geometric means for socio-demographic variables for males, females, and total subjects by analysis of covariance (ANCOVA). Statistical analyses were performed using SPSS version 18.0 (SPSS Inc., Chicago, Ill.). The prevalence of self-reported exposure to SHS was 36.9%. The geometric mean (95% confidence interval) of urine cotinine concentrations among all participants was 16.50 (14.48–18.80) μg/L. Gender, living area, education, and SHS exposure showed significant differences in urine cotinine concentrations. The urine cotinine concentrations of farmworkers and blue-collar workers such as skilled agricultural, forestry, and fishery workers, and elementary occupations were higher than those of white-collar workers such as clerical support workers, technicians, and associate professionals. Such a high proportion of the population having high urine cotinine levels indicates widespread exposure to SHS among nonsmoking workers in Korea. Furthermore, the urine cotinine levels among nonsmoking workers exposed to SHS varied by occupation. The measured urine cotinine concentration is suggested to be a valuable indication of SHS exposure in Korea.

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 aroclor 1254 on the expression of the KAP3 gene and reproductive function in rats

The present study investigated the effects of aroclor 1254 (A1254) on the expression of the kinesin superfamily associated protein 3 (KAP3) gene in F1 rat brain during brain sexual differentiation and puberty. In addition, the effects of A1254 on reproductive function were examined. The KAP3 gene is involved in the neurogenesis and synaptogenesis of sexual differentiation in rats and also during puberty. In the present study, pregnant Sprague-Dawley rats each received a daily dose of A1254 (0, 10, 50 mg kg(-1)) dissolved in 1.0 mL corn oil by gavage, from gestational Day (GD) 8 to postnatal Day (PD) 21. The mRNA levels of the KAP3 gene in hypothalamic tissues were analysed by northern blot hybridisation during the critical periods of brain sexual differentiation (GD18 and PD5) and puberty (PD28). Variables affecting reproduction in F1 female rats, such as vaginal opening (VO), vaginal oestrus (VE) and oestrous cyclicity, were recorded. Depending on the sex and A1254 exposure (control or 50 mg kg(-1) day(-1)), F1 rats were divided into three mating groups, namely control male-control female, control male-A1254-treated female and A1254-treated male-control female. During the critical periods of brain sexual differentiation (GD18, PD5) and puberty (PD28), KAP3 mRNA levels were significantly reduced in A1254-treated fetal and pubertal rat brains relative to those of control groups. In A1254-treated F1 female rats, VO and VE were delayed, the percentage of irregular oestrous cycles was increased and the duration of the oestrous cycle was extended in a dose-dependent manner compared with control groups. Treatment with a high dose of A1254 significantly impaired the reproductive function of both male and female F1 rats, including mating and pregnancy indices and the number of live fetuses. These data suggest that A1254 disrupts transcriptional regulation of the KAP3 gene in fetal and pubertal rat brains and that these effects may be related to A1254-induced abnormal brain sexual differentiation and lowered reproductive function in F1 rats.

Serum concentrations of per- and poly-fluoroalkyl substances and factors associated with exposure in the general adult population in South Korea

Per- and polyfluoroalkyl substances (PFASs) are ubiquitous contaminants found worldwide, including in South Korea. As a result, they are frequently detected in Koreans. However, there is limited representative data and information on potential sources in Korea. Therefore, we measured the serum concentrations of ten PFASs in nationally representative samples of the Korean population (n=1874, 18-69 years) and evaluated the factors associated with their exposure. Serum PFOS, PFDA, PFOA, and PFNA were detected in nearly all participants (83.1-99.9%). However, serum PFPA, PFHxA, and PFHpA were almost undetected (<0.5% of participants). PFOS had the highest population-weighted geometric mean of 10.23ng/mL (95% CI: 9.99-10.47), which was followed by PFOA with 2.85ng/mL (95% CI: 2.73-2.97) and PFDA with 2.17ng/mL (95% CI: 2.12-2.23). PFNA, PFDA, PFHxS, PFOA, and PFOS concentrations were higher in males (p<0.001) and older adults (p<0.001). PFNA was higher in those who used wax, polish, and water-resistant materials (adjusted proportional change=1.14; 95% CI: 1.08-1.22), and those who ate cooked fish (1.16; 95% CI: 1.03-1.31) compared to those who ate nearly no fish. PFDA was higher in those who used herbicides and pesticides (1.05; 95% CI: 1.02-1.09), those who drank beverages in a plastic bag on a daily basis (1.10; 95% CI: 1.03-1.19), and those who ate raw fish (1.15; 95% CI: 1.03-1.29) or cooked fish (1.13; 95% CI: 1.05-1.23) compared to those who ate nearly no fish. PFHxS was higher in those who used traditional Korean health supplement foods (1.08; 95% CI: 1.01-1.15). PFOA was higher in those who used plastic wrap in a microwave daily or weekly (1.08; 95% CI: 1.00-1.16), and those who used disposable paper cups (1.07; 95% CI: 1.01-1.13). PFOS was lower in underweight participants (0.84; 95%CI: 0.75-0.93) compared to those who were obese, and higher in those who exercised regularly (1.08; 95% CI: 1.03-1.14) or irregularly (1.06, 95% CI: 1.01-1.12) compared to those who did not exercise. Subjects who used severely damaged Teflon appliances had lower concentrations of PFOA (0.78, 95% CI: 0.65-0.95), while regular use of Gore-Tex goods was related to higher PFNA (1.15, 95% CI: 1.03-1.28) and PFDA (1.11; 95% CI: 1.02-1.20) levels. These findings suggest that most Koreans are frequently exposed to PFASs, and that serum concentrations of PFASs vary with age, sex, and exposure factors.

Neuroprotective effect of rice bran extract supplemented with ferulic acid in the rat model of ischemic brain injury

Cerebral ischemia is clinically characterized by a partial functional neurological deficit, which represents one of the leading causes of death. This study aimed to determine whether rice bran extract (RB), ferulic acid (FA), or rice bran extract supplemented with FA (RB + FA) promote functional recovery from ischemic injury. Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in rats. Four groups were studied, including (1) vehicle group, (2) RB 5%, 10%, and 20% groups, (3) FA group, and (4) RB + FA group. Animals were injected with RB or FA once a day for 3 days after MCAO. In this studys results, the RB 20% and FA groups significantly improved neurological functions compared with the vehicle group. The RB + FA group produced more recovery from functional deficits than the other groups. Moreover, the RB 20%, FA, and RB + FA groups enhanced the antiapoptotic effect in the cortex and neural cell densities in the hippocampal DG and CA1. The RB 20%, FA, and RB + FA groups stimulated not only the expression of neurotrophic factor and antioxidant genes but also neuronal nuclei (NeuN), synaptophysin, and glutamic acid decarboxylase 67 (GAD67) proteins. Our finding indicates that the combination of RB + FA treatment showed the most synergic effect in functional recovery with ischemic brain through the stimulation of the nuclear factor-E2-related factor 2, brain-derived neurotrophic factor NeuN, SYP, and GAD67 expressions.