Prenatal exposure to low-dose di-(2-ethylhexyl) phthalate (DEHP) induces potentially hepatic lipid accumulation and fibrotic changes in rat offspring.

Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer that is widely used to enhance the flexibility and durability of various products. As an endocrine disruptor, DEHP can interfere with normal hormonal functions, posing substantial health risks to organisms. Given the critical role of the liver in DEHP metabolism, we investigated potential liver damage in offspring induced by prenatal exposure to low doses of DEHP in Sprague Dawley rats. Pregnant rats were divided into three groups and administered 20 or 200 µg/kg/day of DEHP or corn oil vehicle control via oral gavage from gestation days 0-20. Male rat offspring were euthanized on postnatal day 84, and blood and liver specimens were collected for analysis. We observed fibrotic changes in the livers of the exposed groups, accompanied by the proliferation and activation of hepatic stellate cells and upregulated expression of TGF-B and collagen 1A1. Additionally, an inflammatory response, characterized by increased macrophage infiltration and elevated levels of pro-inflammatory cytokines, was evident. Third, hepatic and serum triglyceride and serum cholesterol were notably increased, along with upregulated expression of lipid metabolism-related proteins, such as sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase, fatty acid synthase, and diacylglycerol O-acyltransferase 1, particularly in the low-dose group. These results suggest that prenatal exposure to DEHP can disrupt lipid metabolism, resulting in hepatic lipid accumulation in the offspring. This exposure may also induce an inflammatory response that contributes to the development of liver fibrosis. Thus, even at relatively low doses, such exposure can precipitate latent liver damage in offspring.

Epigenetic transgenerational effects of PM2.5 collected from southern Taiwan on sperm functions and DNA methylation in mouse offspring.

During respiration, particulate matter with a diameter of 2.5 µm or less (PM2.5) suspended in the atmosphere enters the terminal alveoli and blood. PM2.5 particles can attach to toxic substances, resulting in health problems. Limited information is available regarding the effects of prenatal exposure to water-soluble PM2.5 (WS-PM2.5) and water-insoluble PM2.5 (WI-PM2.5) on male reproduction. In addition, whether exposure to these particles has transgenerational effects remains unknown. We investigated whether prenatal exposure to WS-PM2.5 and WI-PM2.5 disrupts sperm function in generations F1, F2, and F3 of male mice. Pregnant BALB/c mice were treated using intratracheal instillation on gestation days 7, 11, and 15 with 10 mg of a water extract or insoluble PM2.5. On postnatal day 105, epididymal sperm count, motility, morphology, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, the sperm chromatin DNA fragmentation index (DFI), and testicular DNA methyltransferase (Dnmt) levels were evaluated in all generations. Whole-genome bisulfite sequencing was used to analyze the DNA methylation status of generation F3. According to the results, exposure to WS-PM2.5 affected sperm morphology, ROS production, and mean DFI in generation F1; ROS production and mean DFI in generation F2; and sperm morphology and MMP in generation F3. Similarly, exposure to WI-PM2.5 affected sperm morphology, ROS production, mean DFI, %DFI, and Dnmt1 expression in generation F1; sperm morphology, MMP, and ROS production in generation F2; and sperm morphology, ROS, and %DFI in generation F3. Two hypermethylated genes, PRR16 and TJP2, were observed in the WS-PM2.5 and WI-PM2.5 groups, two hypomethylated genes, NFATC1 and APOA5, were observed in the WS-PM2.5 group, and two hypomethylated genes, ZFP945 and GSE1, were observed in the WI-PM2.5 group. Hence, prenatal exposure to PM2.5 resulted in transgenerational epigenetic effects, which may explain certain phenotypic changes in male reproduction.

Exposure to tris(2-butoxyethyl) phosphate induces abnormal sperm morphology and testicular histopathology in male rats.

Tris(2-butoxyethyl) phosphate (TBEP) is one of the most abundant organophosphate flame retardants in the environment. This study aimed to evaluate the effect of TBEP exposure during adolescence on male reproductive function in adult rats. Male Sprague-Dawley rats were treated with 20 and 200 mg/kg body weight of TBEP or corn oil from postnatal day (PND) 42 to PND 105. A significant increase in the proportion of sperm with abnormal morphology (flattened head and bent tail) and superoxide anion (O2-.) production in the sperm of the 200 mg/kg treated group was observed (p < 0.05). Excessive production of sperm hydrogen peroxide (H2O2) was found in both the 20 and 200 mg/kg treatment groups (p < 0.05). Disruption of testicular structure was observed in the 20 and 200 mg/kg treated groups and seminiferous tubule degeneration was observed in the 200 mg/kg treated group. Our study demonstrated the adverse effects of TBEP on male reproductive function in rats.

Repeated exposure to fine particulate matter constituents lead to liver inflammation and proliferative response in mice.

BACKGROUND: Fine particulate matter (particulate matter with aerodynamic diameter of ≦2.5 µm, PM2.5) exposure cause adverse health effects, including lung inflammation. Through intra-tracheal instillation of PM2.5 components, the study aimed to evaluate the inflammatory and proliferative effects on mice liver. PM2.5 samples were collected near an industrial complex at southern Taiwan. Mice were exposed to water extracts or insoluble particles by intra-tracheal instillation. Male C57BL/6 mice were divided into five groups: control, low dose insoluble particle exposure (LP), high dose insoluble particle exposure (HP), low dose water extract exposure (LW), and high dose water extract exposure (HW). Biochemical analysis, western blotting, histological examination, and immunohistochemistry were employed to evaluate the results. RESULT: Enrichment factor (EF) of metallic elements showed that the EFs of trace elements (Ti, V, Ni, Zn, Pb, Cr, and Cu) in PM2.5 were above 10. Hematoxylin and Eosin (H&E) staining of the liver tissue showed inflammatory infiltration in particle exposure group; hepatocyte ballooning degeneration and karyomegaly were seen in the water extract exposure group. Upregulation of inflammatory signaling, p65 and p50, and caspase-3 (an important effector involved in apoptosis) positive hepatocytes was significantly increased in the HP group, followed by an elevation in protein levels of growth arrest and DNA damage-inducible protein 153 (GADD153). Increased protein expression of proliferating cell nuclear antigen (PCNA) was noted in the LW and HW groups. An increase in phosphorylation of regulators of cell proliferation, Akt and extracellular signal-regulated kinase (ERK) 1/2, were detected in the LW and HW groups. CONCLUSION: The present study shows that the insoluble particle composition of PM2.5 induced inflammatory signaling and cytokines upregulation in the liver, accompanied with inflammatory cell and macrophage infiltration and an abnormal liver function. Exposure of water extract to PM2.5 induced signals of upregulated cellular proliferation, elevated markers of cell proliferation in liver, hepatocyte ballooning degeneration and karyomegaly.

Transgenerational Effects of Di(2-Ethylhexyl) Phthalate on Anogenital Distance, Sperm Functions and DNA Methylation in Rat Offspring.

Di(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in the manufacture of polyvinylchloride plastics and has been associated with concerns regarding male reproductive toxicity. In this study, we hypothesized that maternal exposure to DEHP induces transgenerational inheritance of adult-onset adverse reproductive outcomes through the male germline in the F1, F2, and F3 generations of male offspring. Pregnant rats were treated with 5 or 500 mg of DEHP/kg/day through gavage from gestation day 0 to birth. The offspring body weight, anogenital distance (AGD), anogenital index (AGI), sperm count, motility, and DNA fragmentation index (DFI) were measured for all generations. Methyl-CpG binding domain sequencing was performed to analyze sperm DNA methylation status in the F3. DEHP exposure at 500 mg/kg affected AGD, AGI, sperm count, mean DFI, and %DFI in the F1; AGD, sperm count, and mean DFI in the F2; and AGD, AGI, mean DFI, and %DFI in the F3. DEHP exposure at 5 mg/kg affected AGD, AGI, sperm count, and %DFI in the F1; sperm count in the F2; and AGD and AGI in F3. Compared with the control group, 15 and 45 differentially hypermethylated genes were identified in the groups administered 5 mg/kg and 500 mg/kg DEHP, respectively. Moreover, 130 and 6 differentially hypomethylated genes were observed in the groups administered 5 mg/kg and 500 mg/kg DEHP. Overall, these results demonstrated that prenatal exposure to DEHP caused transgenerational epigenetic effects, which may explain the observed phenotypic changes in the male reproductive system.

Indium acetate toxicity in male reproductive system in rats.

Indium, a rare earth metal characterized by high plasticity, corrosion resistance, and a low melting point, is widely used in the electronics industry, but has been reported to be an environmental pollutant and a health hazard. We designed a study to investigate the effects of subacute exposure of indium compounds on male reproductive function. Twelve-week old male Sprague-Dawley rats were randomly divided into test and control groups, and received weekly intraperitoneal injections of indium acetate (1.5 mg/kg body weight) and normal saline, respectively, for 8 weeks. Serum indium levels, cauda epididymal sperm count, motility, morphology, chromatin DNA structure, mitochondrial membrane potential, oxidative stress, and testis DNA content were investigated. The indium acetate-treated group showed significant reproductive toxicity, as well as an increased percentage of sperm morphology abnormality, chromatin integrity damage, and superoxide anion generation. Furthermore, positive correlations among sperm morphology abnormalities, chromatin DNA damage, and superoxide anion generation were also noted. The results of this study demonstrated the toxic effect of subacute low-dose indium exposure during the period of sexual maturation on male reproductive function in adulthood, through an increase in oxidative stress and sperm chromatin DNA damage during spermiogenesis, in a rodent model.

The adverse effects of low-dose exposure to Di(2-ethylhexyl) phthalate during adolescence on sperm function in adult rats.

Di(2-ethylhexyl) phthalate (DEHP) is the most crucial phthalate derivative added to polyvinyl chloride as a plasticizer. This study examined the effects of low-dose exposure to DEHP during adolescence on sperm function in adult rats. The male rats were daily gavaged with 30, 100, 300, and 1000 µg kg(-1) of DEHP or corn oil from postnatal day (PND) 42 until PND 105. The selection of DEHP doses ranged from the mean daily intake by the normal-population exposure levels to no-observed-adverse-effect level of DEHP for the endpoints evaluated until adulthood. Significant increases in the percentage of sperm with tail abnormality, tendency for sperm DNA fragmentation index (DFI) and percentage of sperm with DFI were found in those exposed to 100, 300, and 1000 µg kg(-1) (P < 0.05). We observed a significant increase of hydrogen peroxide (H2 O2 ) generation in the sperm of the 1000 µg kg(-1) group compared with the control group (P < 0.05). The excessive production of sperm H2 O2 coincided with an increase in sperm DFI. In this study, the lowest-observed-adverse-effect level for sperm toxicity was considered to be 100 µg DEHP/kg/day in sperm morphology and chromatin DNA damage. Further research is necessary to clarify the mechanisms of DEHP-related sperm ROS generation on sperm DNA damage. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 706-712, 2016.

Urinary metabolites of di(2-ethylhexyl) phthalate relation to sperm motility, reactive oxygen species generation, and apoptosis in polyvinyl chloride workers.

PURPOSE: To measure the concentrations of urinary di(2-ethylhexyl) phthalate (DEHP) metabolites in polyvinyl chloride (PVC) workers and a control group for determining the relationship of DEHP exposure to semen quality, sperm reactive oxygen species (ROS) generation, and sperm apoptosis. METHODS: We assessed the metabolites of DEHP, namely urinary mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and semen quality, such as sperm concentration, motility, morphology, ROS generation, and DNA damage by using terminal deoxynucleotidyl transferase-mediated nick end labeling assay obtained from 47 workers employed within two PVC pellet plants and 15 graduate students in Taiwan. RESULTS: Sperm concentration and motility were significantly affected in the high-exposure group. The percentage and intensity of sperm ROS generation were higher in the high-exposure group than those in the control group. After adjustment for age, smoking status, and coffee consumption, the decrease in sperm motility was inversely associated with the concentration of MEHP (ß = -0.549, p = 0.0085), MEHHP (ß = -0.155, p = 0.0074), and MEOHP (ß = -0.201, p = 0.0041). Moreover, sperm apoptosis and ROS generation were positively associated with MEHHP and MEOHP concentration, respectively. CONCLUSIONS: This was the first study to explore the associations between levels of DEHP exposure, sperm motility, ROS generation, and apoptosis. The results suggested that urinary MEHHP and MEOHP were sensitive biomarkers for reflecting the relationship between DEHP exposure and semen quality.

Developmental exposure to decabrominated diphenyl ether (BDE-209): effects on sperm oxidative stress and chromatin DNA damage in mouse offspring.

Polybrominated diphenyl ethers (PBDEs) are used as brominated flame retardants and have been found in human milk in recent years. This study investigates whether prenatal exposure to decabrominated diphenyl ether (BDE-209) induces sperm dysfunction in male offspring. Pregnant CD-1 mice were gavaged once daily with corn oil (control), 10, 500, and 1500 mg kg(-1) body weight of BDE-209 from day 0 of gestation to day 17. The outcomes of male reproductive parameters were assessed on postnatal day 71. Anogenital distance, sperm-head abnormalities, and testicular histopathology were significantly affected in male offspring prenatally exposed to 1500 mg kg(-1). Significant increases in the tendency for sperm DNA denaturation (αT) induction and the DNA fragmentation index (DFI) were found in those exposed to 10, 500, and 1500 mg kg(-1) (P < 0.05). We observed a significant increase of sperm hydrogen peroxide (H(2)O(2)) generation in the 10 and 1500 mg/kg/day groups compared to the control group (P < 0.05). Although our findings suggested that the mechanisms underlying BDE-209-induced sperm DNA damage and H(2)O(2) generation might not be represented as a dose-response relationship, we found that the greater the excess production of sperm H(2)O(2), the greater the sperm αT (r = 0.65, P = 0.0155) and DFI (r = 0.53, P = 0.002). In conclusion, developmental exposure to BDE-209 induced sperm-head abnormality, oxidative stress, chromatin DNA damage, and testicular histopathological changes. These findings suggest that BDE-209-induced male reproductive effects might involve the formation of sperm H(2)O(2) which attacks nucleic acids via H(2)O(2) generation.

Decreased levels of perfluoroalkyl substances in patients receiving hemodialysis treatment.

Perfluoroalkyl substances (PFAS) have been reported to be harmful to multiple organs in the human body. Based on a previous study suggesting that hemodialysis (HD) may be a means of eliminating PFAS from the human body, we aimed to compare the serum PFAS concentrations of patients undergoing regular HD, patients with chronic kidney disease (CKD) and controls. Additionally, we also investigated the correlation between PFAS and biochemical data, as well as concurrent comorbidities. We recruited 301 participants who had been on maintenance dialysis for >90 days, 20 participants with stage 5 non-dialysis CKD, and 55 control participants who did not have a diagnosis of kidney disease, with a mean creatinine level of 0.77 mg/dl. Eight different PFAS, namely perfluorooctanoic acid (PFOA), total and linear perfluorooctanesulfonic acid (PFOS), perfluoroheptanoic acid (PFHpA), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Spearman correlation and multivariable linear regression with 5 % false discovery rate were used to evaluate the relationships between PFAS and clinical parameters in HD patients and controls. Circulating concentrations of seven PFAS, including total and linear PFOS (T-PFOS and L-PFOS) PFDA, PFNA, PFHxS, PFOA, and PFUnDA, were significantly lower in the HD group compared to the CKD and control group. For the interplay between biochemical data and PFAS, all of the studied PFAS were positively correlated with aspartate aminotransferase, alanine aminotransferase, glucose, blood urea nitrogen, ferritin, and vitamin D in the controls, while in HD patients, the PFAS were all positively correlated with albumin, uric acid, iron, and vitamin D. These findings may offer valuable insights for future studies seeking to eliminate PFAS.

First report of an adult female patient with endobronchial inflammatory myofibroblastic tumor in Taiwan: A case report.

An inflammatory myofibroblastic tumor (IMT) of the respiratory system is an uncommon disease. In Taiwan, there is a lack of previous studies on tracheobronchial IMT. The tumor is characterized by overexpression of anaplastic lymphoma receptor tyrosine kinase (ALK)-1. Surgical resection is the standard treatment of choice nowadays.

Transgenerational effects of BDE-209 on male reproduction in F3 offspring rats.

Decabromodiphenyl ether (BDE-209), a congener of polybrominated diphenyl ethers, is a commonly used brominated flame retardant and a known endocrine disrupting chemical (EDC). Knowledge about the effects of prenatal BDE-209 exposure on male reproduction and whether transgenerational effects occur in subsequent generations are scant. Therefore, in this study, we tested the hypothesis that prenatal exposure to BDE-209 disrupted sperm function in the F1, F2, and F3 generations of male rats. Pregnant Sprague-Dawley rats were treated by gavage from gestation day 0 to birth with 5 mg BDE-209/kg/day. This treatment was based on the lowest-observed-adverse-effect level for DNA damage to sperm in male offspring. On postnatal day 84 for all generations, epididymal sperm counts, motility, morphology, reactive oxygen species generation, sperm chromatin DNA structure integrity, testicular DNA content in spermatogenesis, and serum testosterone levels were assessed. DNA methyltransferase (Dnmts) mRNA expression and methyl-CpG binding domain sequencing were also examined to analyze DNA methylation status in the F3 generation. In the F1 generation, prenatal exposure to BDE-209 disrupted body weight, decreased anogenital distance (AGD), sperm count, and motility; and increased bent tail rates of sperm. In the F2 generation, exposure to BDE-209 decreased AGD, sperm count, normal morphology rates, Dnmt1 expression, and increased Dnmt3a expression. In the F3 generation, BDE-209 exposure decreased AGD and normal sperm morphology, disrupted testicular elongated spermatid and round spermatid rates, reduced serum testosterone levels, and inhibited the mRNA expression of Dnmt1 and Dnmt3b. Compared with the control group, there existed 215 differentially hyper-methylated and 83 hypo-methylated genes in the BDE-209 group. BDE-209 is an EDC to disrupt the male reproduction from F1 to F3. BDE-209-induced changes in sperm function and hyper- or hypo-DNA methylation in the F3 generation might therefore explain the possible mechanism underlying BDE-209-mediated epigenetic transgenerational effects on the male reproductive system.

Association between ambient air pollution and out-of-hospital cardiac arrest: are there potentially susceptible groups?

This study aimed to examine the association between air pollution and out-of-hospital cardiac arrest (OHCA), and the effects of underlying diseases. Between January 2015 and December 2016, data on particulate matter (PM)2.5 and other air pollutants in Kaohsiung City were collected, and an emergency medical service database was used for information on patients who experienced OHCA. Overall, 3566 patients were analyzed and subgroup analyses by sex, age, and preexisting morbidities were performed. Interquartile increments in PM2.5, PM10, and O3 levels on lag 1 and NO2 level on lag 3 were associated with increments of 10.8%, 11.3%, 6.2%, and 1.7% in OHCA incidence, respectively. Subgroup analyses showed that patients with diabetes (1.363; interaction p = 0.009), heart disease (1.612; interaction p = 0.001), and advanced age (≥70 years, 1.297; interaction p = 0.003) were more susceptible to NO2 on lag 3. Moreover, patients were more susceptible to O3 during the cold season (1.194; interaction p = 0.001). We found that PM2.5, PM10, NO2, and O3 may play an important role in OHCA events, and the effects vary by underlying condition, age and season.

Developmental exposure to decabromodiphenyl ether (PBDE 209): effects on thyroid hormone and hepatic enzyme activity in male mouse offspring.

Decabrominated diphenyl ether (PBDE 209) is the second most used brominated flame retardant (BFRs). Many studies have shown that some of the BFRs act as endocrine disruptors via alterations in thyroid hormone homeostasis and affect development. Little is known about the effect of prenatal exposure to PBDE 209 on the development in male offspring. Using a CD-1 mouse model, we attempt to estimate the possible effect of in utero exposure to PBDE 209 on thyroid hormone and hepatic enzymes activities in male offspring. Pregnant mice were administered different doses of PBDE 209 (10, 500, and 1500 mg/kg/day) or corn oil for controls per gavage from gestational days 0-17. In adult male offspring whose mothers had been treated with 1500 mg/kg of PBD 209, hepatic enzyme activity of S9 7-ethoxyresorufin O-deethylase (EROD) was weak but significantly increased (54%). However, no significant changes were observed in S9 4-nitrophenol uridinediphosphate-glucuronosyltransferase (UDPGT) in any of the treatment groups. Serum triiodothyronine (T3) was found to have decreased significantly (ca. 21% both 10 mg/kg and 1500 mg/kg) in offspring, but not thyroxine (T4). Histopathological examination revealed that prenatal exposure of PBDE 209 might be related with cell swelling of hepatocytes in male offspring and there were mild changes in the thyroid glands in 1500 mg/kg group. These data demonstrate that PBDE 209 is likely an endocrine disrupter in male mice following exposure during development. Further studies using environmentally relevant doses are needed for hazard identification.

Phthalate exposure promotes chemotherapeutic drug resistance in colon cancer cells.

Phthalates are widely used as plasticizers. Humans can be exposed to phthalates through ingestion, inhalation, or treatments that release di(2-ethylhexyl) phthalate (DEHP) and its metabolite, mono(2-ehylhexyl) phthalate (MEHP), into the body from polyvinyl chloride-based medical devices. Phthalate exposure may induce reproductive toxicity, liver damage, and carcinogenesis in humans. This study found that colon cancer cells exposed to DEHP or MEHP exhibited increased cell viability and increased levels of P-glycoprotein, CD133, Bcl-2, Akt, ERK, GSK3ß, and ß-catenin when treated with oxaliplatin or irinotecan, as compared to control. The P-glycoprotein inhibitor, tariquidar, which blocks drug efflux, reduced the viability of DEHP- or MEHP-treated, anti-cancer drug-challenged cells. DEHP or MEHP treatment also induced colon cancer cell migration and epithelial-mesenchymal transformation. Elevated stemness-related protein levels (ß-catenin, Oct4, Sox2, and Nanog) and increased cell sphere sizes indicated that DEHP- or MEHP-treated cells were capable of self-renewal. We also found that serum DEHP concentrations were positively correlated with cancer recurrence. These results suggest phthalate exposure enhances colon cancer cell metastasis and chemotherapeutic drug resistance by increasing cancer cell stemness, and that P-glycoprotein inhibitors might improve outcomes for advanced or drug-resistant colon cancer patients.

Induction of apoptosis by Uncaria tomentosa through reactive oxygen species production, cytochrome c release, and caspases activation in human leukemia cells.

Uncaria tomentosa (Wild.) DC., found in the Amazon rain forest in South-America and known commonly as cat's claw, has been used in traditional medicine to prevent and treat inflammation and cancer. Recently, it has been found to possess potent anti-inflammation activities. In this study, we extracted cat's claw using four different solvents of different polarities and compared their relative influence on proliferation in human premyelocytic leukemia HL-60 cell lines. Cat's claw n-hexane extracts (CC-H), ethyl acetate extracts (CC-EA) and n-butanol extracts (CC-B) had a greater anti-cancer effect on HL-60 cells than those extracted with methanol (CC-M). Furthermore, CC-EA induced DNA fragmentation in HL-60 cells in a clearly more a concentration- and time-dependent manner than the other extracts. CC-EA-induced cell death was characterized by cell body shrinkage and chromatin condensation. Further investigating the molecular mechanism behind CC-EA-induced apoptosis, sells treated with CC-EA underwent a rapid loss of mitochondrial transmembrane (DeltaPsi(m)) potential, stimulation of phosphatidylserine flip-flop, release of mitochondrial cytochrome c into cytosol, induction of caspase-3 activity in a time-dependent manner, and induced the cleavage of DNA fragmentation factor (DFF-45) and PARP poly-(ADP-ribose) polymerase (PARP). CC-EA promoted the up-regulation of Fas before the processing and activation of procaspase-8 and cleavage of Bid. In addition, the apoptosis induced by CC-EA was accompanied by up-regulation of Bax, down-regulation of Bcl-X(L) and cleavage of Mcl-1, suggesting that CC-EA may have some compounds that have anti-cancer activities and that further studies using cat's claw extracts need to be pursued. Taken together, the results of our studies show clearly that CC-EA's induction of apoptosis in HL-60 cells may make it very important in the development of medicine that can trigger chemopreventive actions in the body.

Estimation of waste generation from floods.

A framework of correlation for estimating the amount of waste generation from floods is developed. Flood waste data were collected from four recent typhoons in Taiwan. Parameters affecting the flood waste are analyzed. Population density, flooded area and amount of total rainfall are chosen as the correlating parameters for the model development, and regression diagnostics are performed to check the validity of the collected data. The simple linear model is shown to be incapable of correlating the flood waste data. An exponential model is proposed and shown to give acceptable correlation with the flood waste data spanning five orders of magnitude. The model can be useful in the planning of waste cleanup after floods.

Effects of di(2-ethylhexyl)phthalate exposure on 1,2-dimethyhydrazine-induced colon tumor promotion in rats.

Di(2-ethylhexyl)phthalate (DEHP) may cause carcinogenicity in the liver; however, few have detailed on the potential effects of DEHP exposure on colorectal cancer. Male Sprague-Dawley rats received i.p. injections of 1,2-dimethylhydrazine (DMH) once-a-week for the first 4 weeks, and rats in each group were treated with DEHP through oral gavage daily for either 7, 10 or 15 weeks; after which, all rats were euthanized and their colons were assessed (a) morphologically for aberrant crypt foci (ACF) or tumors, (b) cytologically for mitotic index (MI), and (c) immunohistochemically for the expression of ß-catenin, cyclooygenase (COX)-2, vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), cyclin D1, and c-myc. Our results indicated that the mean total ACF, tumor incidence, and MI were significantly higher in the DEHP-treated DMH compared to control and the DEHP-alone groups. The level of ß-catenin and cyclin D1 was increased in DEHP-exposed rats. Expression of ß-catenin, COX-2, VEGF, and cyclin D1 was significantly higher in the combined DMH and DEHP-treated rats by comparison to that of the DMH group. In conclusion, this study indicates that exposure to DEHP may exacerbate DMH-induced colon tumorigenesis and provides impetus to evaluate the effect of DEHP in conjunction with other carcinogens.

Mechanistic study of polychlorinated biphenyl 126-induced CYP11B1 and CYP11B2 up-regulation.

Although polychlorinated biphenyls (PCBs) have been shown to accumulate in the adrenal, little is known about the effects of these endocrine disruptors on adrenal steroidogenesis. Our previous studies showed that high concentrations of PCB126 stimulated CYP11B1 and CYP11B2 mRNA expression and consequently raised cortisol and aldosterone synthesis in the human adrenocortical H295R cells, respectively. In this study, we further investigated the mechanism underlying the PCB126-induced steroidogenic alterations. We first examined the role of the PCB126 nuclear receptor aryl hydrocarbon receptor (AhR) using a potent antagonist 3',4'-dimethoxyflavone (3',4'-DMF). Although 3',4'-DMF abolished AhR-dependent transcriptional activity, it could not block PCB126-stimulated CYP11B1 and CYP11B2 induction. Conversely, 3',4'-DMF synergistically increased the stimulatory effects of PCB126. Furthermore, PCB39, -77, -132, -156, and -169, whether AhR ligands or not, all could increase CYP11B1 and CYP11B2 mRNA accumulation. Promoter analyses demonstrated that PCB126 had little effects on the transcription rate of both genes, whereas RNA degradation assays showed that PCB126 protected both transcripts from degradation. In contrast, 3',4'-DMF exhibited positive effects on transcription but no influence on transcript stability. The synergistic induction of CYP11B1 and CYP11B2 mRNA levels by the PCB126/3',4'-DMF cotreatment might result from the combination of transcriptional regulation by 3',4'-DMF and posttranscriptional regulation by PCB126. This study also demonstrated that an internal region of CYP11B1 mRNA (nucleotides 881-1285) was important for PCB126-mediated transcript stabilization. From these findings, we concluded that PCB126 up-regulated steroidogenic CYP11B1 and CYP11B2 mRNA expression not via AhR-mediated transcriptional activation but by increasing posttranscriptional mRNA stability.

Postnatal exposure of the male mouse to 2,2',3,3',4,4',5,5',6,6'-decabrominated diphenyl ether: decreased epididymal sperm functions without alterations in DNA content and histology in testis.

2,2',3,3',4,4',5,5',6,6'-Decabrominated diphenyl ether (PBDE 209) is the second most used brominated flame retardant (BFRs) in constructed materials because it is considered less toxic than others, though other fire retardants, some congeners of PBDE 209, are reported to be toxic. This combined the fact that PBDE 209 has been found in high levels in human milk, blood, indoor environments as well as in foodstuffs has led us in this study attempt to find out whether PBDE 209, also known as decaBDE and decabrominated diphenyl oxide (DBDPO), has an adverse effect on this histology of testes and sperm in CD-1 male mice. The mice we studied were divided into groups and gavaged with 10, 100, 500 and 1500 mg/kg PBDE 209 in corn oil per day between postnatal Days 21 and 70. On Day 71, the mice were anesthetized and sperm function, testis DNA content, and histopathology were studied. We found in the 500- and 1500-mg/kg/day groups that neonatal exposure to PBDE 209 reduced sperm epididymal sperm mitochondrial membrane potential (MMP), reduced amplitude of the lateral head displacement (ALH) and induced the generation of hydrogen peroxide (H2O2) in the sperm of sexually mature male mice, without affecting the sperm count, motility, morphology, curvilinear velocity (VCL), angular progressive velocity (VAP), straight-line velocity (VSL), beat-cross frequency (BCF), sperm chromatin structure assay (SCSA), superoxide anion (O2-*) generation, DNA content in testis cells, or testicular histopathology. ALH was positively associated with an increase in MMP and negatively associated with generation of sperm H2O2. The reduction of MMP was negatively associated with an increase in generation of sperm H2O2. The presence of the relationships between sperm ALH, MMP, and generation of H2O2 indicate toxic action possibly resulting from PBDE 209-induced oxidative stress. In conclusion, this is the first study to report the lowest-observed-adverse-effect level (LOAEL) for sperm function to be 500 mg/kg of PBDE 209 in male mice. Decreased epididymal sperm MMP and ALH as well as induced generation of sperm H2O2 were some of the most serious effects of postnatal PBDE 209 exposure. Future investigations should be performed to study the effects of prenatal exposure of PBDE 209 and the mechanism behind PBDE 209-related oxidative stress in the fetal and pubertal stages of development.