Publications by authors named "Wei-Hsiang Chang"

22 Publications

  • Page 1 of 1

Cumulative risk assessment of phthalates exposure for recurrent pregnancy loss in reproductive-aged women population using multiple hazard indices approaches.

Environ Int 2021 May 27;154:106657. Epub 2021 May 27.

Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan. Electronic address:

Phthalates, which are commonly used in flexible plastics and consumer products, have been reported to be toxic to reproductive and developmental function in mammals. Past studies have focused on the toxic effects on male reproduction, with only a few studies conducted on the risks that cumulative exposure to phthalates have on the female reproductive system. We recruited 260 patients with recurrent pregnancy loss (RPL) of unknown etiology and 203 controls from the clinics of Obstetrics and Gynecology at a medical center in southern Taiwan from 2013 to 2020. The daily intake of phthalates was estimated from urine samples using the back-calculation method, after which the cumulative risk was determined using multiple hazard indices, including a dose-addition model, a receptor effect model, and a hazard index approach. The patients with RPL had a significantly higher cumulative exposure to phthalates (p < 0.05) than did the controls with a hazard index above one. After adjusted logistic regression analysis, we found that the risk of RPL was strongly related to the higher quartiles of DEHP, the DEHP for the antiandrogenic effect and adverse effects of the female reproductive system and the ER binding effect (p < 0.05). Our work suggests that more attentions should be paid to the adverse effects induced by phthalates on female reproduction, especially the effects caused by the cumulative exposure to phthalates in women of reproductive age.
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http://dx.doi.org/10.1016/j.envint.2021.106657DOI Listing
May 2021

Human biomonitoring reference values and characteristics of Phthalate exposure in the general population of Taiwan: Taiwan Environmental Survey for Toxicants 2013-2016.

Int J Hyg Environ Health 2021 May 26;235:113769. Epub 2021 May 26.

Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan. Electronic address:

Since a 2011 incident involving phthalate-tainted food, Taiwanese people have become concerned with food quality, and they are still being exposed to certain levels of phthalates. However, no nationwide human biomonitoring survey had been conducted to gather information on levels or reference values (RVs) of phthalates in the Taiwanese population. We aimed to establish the urinary levels and RVs of phthalate metabolites and identify exposure characteristics among Taiwan's population. We enrolled 1857 participants 7 years of age and older from the Taiwan Environmental Survey for Toxicants (TESTs) conducted during 2013-2016. Levels of 11 phthalate metabolites in each participant's urine samples were determined using liquid chromatography-tandem mass spectrometry. For all phthalate metabolites except for mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), and mono-ethylhexyl phthalate (MEHP), urinary median levels were significantly higher in the 7-17-year old group than in the ≧18-year-old group. For most phthalate metabolites and in the general population, the geometric mean decreased with increasing age. Median levels of MEP (19.55 μg/L), mono-benzyl phthalate (MBzP) (2.11 μg/L), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (22.82 μg/L), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEOHP) (16.08 μg/L), ΣDibutyl phthalate metabolites (ΣDBPm) (0.17 nmol/mL), Σdi-(2-ethylhexyl) phthalate metabolites (ΣDEHPm) (0.29 nmol/mL) were higher in participants from central Taiwan than those from other areas. The median level of DBP (ΣDBPm: 0.20 nmol/mL) was significantly higher in participants from harbor areas than those from other urbanization groups. The RV of the 95 percentile (P) for phthalate metabolites in the 7-17/≧18-year-old groups were 185.95/208.19 μg/L for MMP, 198.46/265.81 μg/L for MEP, 119.85/69.99 μg/L for mono-isononyl phthalate (MiBP), 165.19/204.32 μg/L for Mono-n-butyl phthalate (MnBP), 15.61/11.73 μg/L for MBzP, 62.09/59.23 μg/L for MEHP, 149.70/69.66 μg/L for MEHHP, 112.06/35.07 μg/L for MEOHP, 195.20/93.83 μg/L for mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), 45.66/27.69 μg/L for mono-(2-carboxymethylhexyl) phthalate (MCMHP), and 9.09/12.13 μg/L for mono-iso-nonyl phthalate (MiNP). We concluded that phthalate exposure of the general population in Taiwan varies by sex, age, region, and urbanization level. Exposure by the 7-17-year-old group to DMP, DBP, and DEHP in Taiwan remains higher than that of youth from other countries. RV of phthalate metabolites in Taiwan were established in the current study.
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http://dx.doi.org/10.1016/j.ijheh.2021.113769DOI Listing
May 2021

The effects of phthalate ester exposure on human health: A review.

Sci Total Environ 2021 Sep 28;786:147371. Epub 2021 Apr 28.

Department of Food Safety/Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Research Center of Environmental Trace Toxic Substances, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. Electronic address:

Phthalate esters (PAEs) are one of the most widely used plasticizers in polymer products and humans are increasingly exposed to them. The constant exposure to PAEs-contained products has raised some concerns against human health. Thus, the impacts of PAEs and their metabolites on human health require a comprehensive study for a better understanding of the associated risks. Here, we attempt to review eight main health effects of PAE exposure according to the most up-to-date studies. We found that epidemiological studies demonstrated a consistent association between PAE exposure (especially DEHP and its metabolites) and a decrease in sperm quality in males and symptom development of ADHD in children. Overall, we found insufficient evidence and lack of consistency of the association between PAE exposure and cardiovascular diseases (hypertension, atherosclerosis, and CHD), thyroid diseases, respiratory diseases, diabetes, obesity, kidney diseases, intelligence performance in children, and other reproductive system-related diseases (anogenital distance, girl precocious puberty, and endometriosis). Future studies (longitudinal and follow-up investigations) need to thoroughly perform in large-scale populations to yield more consistent and powerful results and increase the precision of the association as well as enhance the overall understanding of potential human health risks of PAEs in long-term exposure.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147371DOI Listing
September 2021

Prenatal Phthalates Exposure and Cord Thyroid Hormones: A Birth Cohort Study in Southern Taiwan.

Int J Environ Res Public Health 2021 04 19;18(8). Epub 2021 Apr 19.

Research Center of Environmental Trace Toxic Substances, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Background: The regulation of thyroid hormones in the early stages of gestation plays a crucial role in the outcome of a pregnancy. Furthermore, thyroid hormones are fundamental for the fetal development of all organs, including endocrine hormone changes in uterus. Endocrine disrupting chemicals have been shown to have an effect on thyroid hormone homeostasis in newborns, which affects their later development. Few studies have proposed how phthalates could alter thyroid function through several mechanisms and the possible effects on thyroid hormone homeostasis of phthalates on pregnant women. However, the effects of cord blood phthalates and prenatal phthalate exposure on thyroid hormones in newborns remain unclear.

Objectives: We aim to follow up on our previous established subjects and determine the correlation between phthalate exposure and thyroid hormones in pregnant women and newborns.

Materials And Methods: We recruited 61 pregnant women from the Obstetrics and Gynecology Department of a medical hospital in southern Taiwan and followed up. High performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was used to analyze urine samples for five phthalate metabolites. Serum levels of thyroid hormones were analyzed using electrochemoluminescence immunoassay (ECLIA) method. We used Spearman and Pearson correlation coefficients to evaluate the correlation between each phthalate metabolites in serum and the thyroid hormone levels in fetus and parturient. Finally, multiple logistic regression was used to explore the relationship between hormones and their corresponding phthalate metabolites in cord blood.

Results: High MBP in cord blood was correlated with negative cord serum TSH in newborns (r = -0.25, < 0.06). By using multiple linear regression after adjusting for potential confounders (gestational and maternal age), cord serum MBP levels showed a negative association with cord serum TSH (β = 0.217, < 0.05), cord serum T (β = 1.71, < 0.05) and cord serum T × TSH (β = 42.8, < 0.05), respectively.

Conclusion: We found that levels of cord serum TSH and T in newborns was significantly negatively associated with cord serum MBP levels after adjusting for significant covariate. The fall in TSH in newborns may potentially be delaying their development.
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http://dx.doi.org/10.3390/ijerph18084323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074059PMC
April 2021

Dietary exposure assessment to perchlorate in the Taiwanese population: A risk assessment based on the probabilistic approach.

Environ Pollut 2020 Dec 23;267:115486. Epub 2020 Aug 23.

Research Center of Environmental Trace Toxic Substances, National Cheng Kung University, Tainan, 701, Taiwan; Department of Environmental and Occupational Health, Medical College, National Cheng Kung University, Tainan, 704, Taiwan. Electronic address:

Perchlorate is an endocrine-disrupting chemical (EDC) that contaminate various foodstuffs. Exposure to perchlorate may cause severe health problems, mainly thyroid dysfunction. However, information on perchlorate contamination of consumer foods in Taiwan is limited. This study investigated perchlorate levels in 310 food samples belonging to 12 food groups collected from Taiwanese markets. A probabilistic risk assessment was conducted to assess the related exposure to Taiwanese people. Perchlorate was detected in 65% of the samples and high levels were identified in certain plant-origin, fruit, and processed food samples. A probabilistic approach was used to estimate daily dietary dose (Monte Carlo-estimated 95th percentile dietary exposure [MCS 95]) by using the Taiwan National Food Consumption database for 14 sex/age groups. The highest and lowest average daily doses (ADDs) were in the age groups of >65 years (MCS 95 = 3.60/3.90 [male/female] μg/kg bw/day) and 16-18 years (MCS 95 = 1.70/1.47 [M/F] μg/kg bw/day), respectively. The 95th percentile of the hazard index of exposure to perchlorate of all sex/age groups far exceeded the tolerable daily intake (0.3 μg/kg bw/day) and reference dose (0.7 μg/kg bw/day) set by the European Food Safety Authority and US EPA, respectively, but it was lower than the provisional maximum tolerable daily intake (10 μg/kg bw/day) suggested by the Joint FAO/WHO Expert Committee on Food Additives. The intake quantity and concentrations of perchlorate from vegetables, fruits, and whole grains are the critical contributors for the ADDs and integrated risk of dietary exposure to perchlorate. Long-term exposure through diets should be considered, instead of focusing on individual EDC during dietary risk assessment in specific populations. Furthermore, cumulative risks for exposure to multiple contaminants, particularly those causing thyroid adverse effects, may be higher than that from perchlorate exposure alone.
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http://dx.doi.org/10.1016/j.envpol.2020.115486DOI Listing
December 2020

Urinary phthalate metabolites are associated with biomarkers of DNA damage and lipid peroxidation in pregnant women - Tainan Birth Cohort Study (TBCS).

Environ Res 2020 09 2;188:109863. Epub 2020 Jul 2.

National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address:

Phthalate exposure and oxidative stress have been linked to adverse reproductive outcomes in experimental studies, whereas no clear line has been drawn for human, especially in pregnant women. This study explored relationships between urinary phthalate metabolites and biomarkers of lipid peroxidation and oxidative and nitrosative DNA damage. Measurements from 97 Taiwanese pregnant women were taken at three different times during second and third trimesters. Five oxidative/nitrosative stress biomarkers - 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NOGua), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), 8-isoprostaglandin F (8-isoPF), and malondialdehyde (MDA), and 11 phthalate metabolites were measured in urine samples. Linear regressions in each visit and linear mixed-model regressions were fitted to estimate percent changes in oxidative/nitrosative stress biomarkers resulting from inter-tertile increase of phthalate metabolite level and the cumulative concentrations of di (2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate. The highest urine concentrations of phthalate metabolites and the greatest number of significant positive associations between phthalate metabolites and oxidative/nitrosative stress biomarkers were observed in the third visit and in repeated measurements analysis, respectively. Of the biomarkers related to DNA damage, 8-OHdG (25.4% inter-tertile increase for mono-iso-butyl phthalate) was more sensitive to phthalate exposure than 8-NO2Gua. Among the biomarkers of lipid peroxidation, HNE-MA (61.2% inter-tertile increase for sum of DEHP metabolites) was more sensitive than 8-isoPF and MDA. Our findings support the hypothesis that pregnant phthalate exposure increases the oxidative stress biomarkers of DNA damage and lipid peroxidation. Future research may elucidate the mediating roles of oxidative/nitrosative stress biomarkers in the link between phthalate exposure and adverse reproductive outcomes.
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http://dx.doi.org/10.1016/j.envres.2020.109863DOI Listing
September 2020

Characterization of phthalate exposure in relation to serum thyroid and growth hormones, and estimated daily intake levels in children exposed to phthalate-tainted products: A longitudinal cohort study.

Environ Pollut 2020 Sep 24;264:114648. Epub 2020 Apr 24.

School of Food Safety, College of Nutrition, Taipei Medical University, Taipei, Taiwan. Electronic address:

Background: No information is available on the long-term effects on thyroid and growth hormones of children exposed to phthalate-tainted products, despite the infamous 2011 Taiwan phthalate episode. We investigated estimated daily intake levels and their long-term effects on serum thyroid and growth hormone levels in children.

Methods: We recruited 166 children (2-18 years old) in three visits who provided specimens and filled out a questionnaire from the Risk Assessment of Phthalate Incident in Taiwan (RAPIT) project study from 2012 to 2016. Morning spot urine samples were analyzed for nine phthalate metabolites. Serum thyroid (triiodothyronine [T], thyroxine [T], and free T) and growth hormone (insulin-like growth factor-1 [IGF-1] and its binding protein 3 [IGF-BP3]) levels were measured. A generalized estimating equation model was used to evaluate associations between phthalate metabolite levels and children's thyroid and growth hormone levels.

Results: The median metabolite levels of monomethyl phthalate (MMP), Σdibutyl phthalate (DBP), and Σdi-(2-ethylhexyl) phthalate (DEHP) at visits 1, 2, and 3 were 6.59, 10.5, and 21.0 ng/mL, 0.15, 0.24, and 0.20 nmol/mL, and 0.15, 0.17, and 0.12 nmol/mL, respectively. After adjusting for potential confounding factors, we found that levels of urinary MMP were negatively associated with T (β = -0.013, p = 0.047), T (β = -0.016, p = 0.006), free T (β = -0.012, p = 0.002), and IGF-BP3 (β = -0.025, p = 0.003). Urinary mono-ethyl phthalate (MEP) was negatively associated with IGF-1 (β = -0.027, p = 0.029) and IGF-BP3 (β = -0.016, p = 0.018). In addition, serum free T was positively associated with urinary mono-2-ethyl-5-hydroxy hexyl phthalate (MEHHP) (β = 0.016, p = 0.043), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (β = 0.015, p = 0.024), and ΣDEHPm (β = 0.019, p = 0.020).

Conclusions: Our findings support the hypothesis that specific phthalates disturb the hemostasis of thyroid and growth hormone levels in children exposed to phthalate-tainted products.
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http://dx.doi.org/10.1016/j.envpol.2020.114648DOI Listing
September 2020

Dietary exposure and risk assessment of exposure to hexabromocyclododecanes in a Taiwan population.

Environ Pollut 2019 Jun 14;249:728-734. Epub 2019 Mar 14.

Department of Food Safety/Hygiene and Risk Management, National Cheng Kung University, Tainan, 701, Taiwan; Research Center of Environmental Trace Toxic Substances, National Cheng Kung University, Tainan, 701, Taiwan. Electronic address:

Hexabromocyclododecane (HBCD) is commonly used in commercial products and factories. HBCDs can be detected in the air, bioaccumulated deposits, water, soil, sediments, and in biota and foodstuffs in the food-chain because they are not chemically bound to the polymer. We determined the levels of α-, β-, and γ-HBCDs in 270 foodstuffs and the doses of HBCDs Taiwanese are normally exposed to. We also wanted to create a strategy of risk management for HBCDs based on margins of exposure (MOE). HBCDs were frequently detectible in fish, seafood, and poultry. Their highest concentrations were in fish, oil, poultry, and livestock. The highest estimated daily intake was in 0- to 3-year-olds (1.576 ng/kg/day), and lower in 3- to 6- (1.064 ng/kg/day), 6- to 12- (0.899 ng/kg/day), and lowest in 12- to 16- (0.632 ng/kg/day) year-olds. The exposure doses to HBCDs indicated no health concern for Taiwanese. Except for fish, significant concentrations of α- and γ-HBCDs were detected in many other foodstuffs, which might indicate that exposure to HBCD is a relatively recent problem. Therefore, one goal of a management policy should be to follow-up the flow direction of HBCDs in Taiwan.
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http://dx.doi.org/10.1016/j.envpol.2019.03.040DOI Listing
June 2019

Sex hormones and oxidative stress mediated phthalate-induced effects in prostatic enlargement.

Environ Int 2019 05 22;126:184-192. Epub 2019 Feb 22.

Research Center of Environmental Trace Toxic Substance, National Cheng Kung University, Tainan, Taiwan; Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Prostatic enlargement might affect up to 30% of men and can cause signs and symptoms in the lower urinary tract in the elderly. Imbalanced estrogen and androgen secretions are important in prostatic physiopathology. Phthalates-environmental endocrine disruptors-affect androgen secretion and disrupt sexual organs, including testes and the prostate, but the underlying mechanisms are unclear. Using European Association of Urology (EAU) guidelines, we recruited from urology clinics in southern Taiwan 207 elderly men diagnosed with benign prostatic hyperplasia (BPH) and prostatic enlargement between 2015 and 2017. We took blood and urine samples from all patients on the same day. We used multivariate linear regression, associations, and potential interactions after we had measured and analyzed oxidative stress (OS) markers, steroidal hormones, and 11 urinary phthalate metabolites, and then we adjusted for confounders. Di(2-ethylhexyl) phthalate (DEHP) metabolite levels, particularly urinary mono-(2-ethylhexyl) phthalate, were positively associated with androgen, estrogen, hormone ratios, inducible nitric oxide synthetase (iNOS), 8-hydroxy-2'-deoxyguanosine (8-OHdG), prostate specific antigen (PSA), and prostate volume (PV) (p < 0.05). PV and PSA were positively associated with androgen, estrogen, hormone ratios and OS markers (p < 0.05). The estimated percentages of exposure to phthalates in prostatic enlargement mediated by androgen, estrogen, and OS markers ranged from 3.5% to 63.1%. Exposure to DEHP promoted the progress of BPH by increasing dihydrotestosterone (DHT), estradiol (E), the converted enzymes aromatase and 5α reductase, and reactive oxygen species (ROS) (8-OHdG and iNOS) production. Sex hormones and OS might be important hyperplasia-promoters after a patient has been exposed to phthalates, especially to DEHP.
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http://dx.doi.org/10.1016/j.envint.2019.02.006DOI Listing
May 2019

Dietary intake of 4-nonylphenol and bisphenol A in Taiwanese population: Integrated risk assessment based on probabilistic and sensitive approach.

Environ Pollut 2019 Jan 10;244:143-152. Epub 2018 Oct 10.

Research Center of Environmental Trace Toxic Substances, National Cheng Kung University, Tainan, 701, Taiwan; Department of Environmental and Occupational Health, Medical College, National Cheng Kung University, Tainan, 704, Taiwan. Electronic address:

4-Nonylphenol (NP) and bisphenol A (BPA) are high-production and high-volume chemicals used to manufacture various commercial products. They are also ubiquitous contaminants that disrupt endocrine systems in wildlife and humans. We collected, from Taiwan cities with the highest food production, and analyzed, using high performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS), 278 food samples for NP and BPA from 11 categories. We found background levels of 100% for NP and 72% for BPA in total samples. High levels of contamination (up to 918 and 49.4 μg/kg) were found in some foods of seafood and animal origin. We used a probabilistic approach to calculate daily dietary dose (Monte Carlo-estimated 95th percentile dietary exposure [MCS 95]) from the Taiwan National Food Consumption database for each sex- and age-specified population. For NP and BPA, the highest average daily dose (ADDs) were in the 4- to 6-year-old group (MCS 95 = 1.57/1.28 and 0.157/0.147 [Male/Female] μg/kg bw/day, respectively), and the lowest ADDs were in the ≥65-year-old group (MCS 95 = 0.674/0.581 and 0.054/0.045 [M/F] μg/kg bw/day, respectively). Based on the European Food Safety Authority (4 μg/kg bw/day for BPA) and Danish Institute of Safety and Toxicology guidelines (5 μg/kg bw/day for NP), the 95th percentile HQ of NP and BPA intake in different sex- and age-specified groups in Taiwan posed no risks through dietary exposure. The intake quantity and concentrations of grains, livestock, and seafood are important variables for the integrated risk of NP and BPA. In conclusion, a combination of multiple and long-term exposure via food consumption should be considered rather than individual endocrine-disrupting chemicals during dietary risk assessment in specific populations. SUMMARY: The 95th percentile HQ of NP and BPA intake in different age and sex groups in Taiwan posed no risks through dietary exposure based on probabilistic and sensitive approach.
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http://dx.doi.org/10.1016/j.envpol.2018.10.040DOI Listing
January 2019

DDR2 overexpression in oral squamous cell carcinoma is associated to lymph node metastasis.

Cancer Biomark 2018 ;22(4):747-753

Department of Surgical Pathology.

Background: Discoidin domain receptors (DDRs), a collagen receptor tyrosine kinase, play a major role in cancer progression. DDR2 has been suggested as a prognostic marker in several cancer types; however, the correlation between DDR2 expression and clinical outcome of oral cancer patients in Taiwan population has not been investigated.

Materials And Methods: In the present study we sought to determine the clinical significance of Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2) expression in oral squamous cell carcinoma (OSCC) patients. We examined DDR2 expression in OSCC specimens by immunohistochemistry and then we analyzed the association of DDR2 expression with clinicopathological factors in OSCC.

Results: We divided 254 OSCC cases into two groups based on DDR2 expression levels and compared with several clinicopathological factors and their overall survival. The group with high DDR2 expression had significantly higher frequencies of lymph node metastasis (P= 0.0094) and AJCC stage (P= 0.0058) compared to the group with low DDR2 expression. Furthermore, the lymph node metastasis oral cancer patients with high DDR2 expression had low survival rate than low DDR2 group (P= 0.0458).

Conclusions: Our data indicate that DDR2 is a potent biomarker that can be used as an effective therapeutic target for treating OSCC patients with lymph node metastasis.
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http://dx.doi.org/10.3233/CBM-181302DOI Listing
November 2018

Semen quality and insulin-like factor 3: Associations with urinary and seminal levels of phthalate metabolites in adult males.

Chemosphere 2017 Apr 16;173:594-602. Epub 2017 Jan 16.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan; Research Center of Environmental Trace Toxic Substance, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan. Electronic address:

Certain phthalates have adverse effects on male reproductive functions in animals, and potentially affect human testicular function and spermatogenesis, but little is known about the active mechanisms. We measured the urinary and seminal phthalate metabolites and explored their associations on insulin-like factor 3 (INSL3) and semen quality. Urine, blood, and semen samples were collected from the male partners of subfertile (n = 253) and fertile (n = 37) couples in a reproductive center in southern Taiwan. INSL3, reproductive hormones, semen-quality, and 11 phthalate metabolites in urine and semen were measured. There were significant correlations in the distribution pattern of metabolites, such as the relative contribution of low or high molecular weight phthalate metabolites. The significantly monotonic trends in semen volume, sperm concentration and motility were associated with increasing quartiles of INSL3 (all p-trend < 0.001). In adjusted regression models, increases in urinary phthalate metabolites levels were adversely associated with sperm concentration (monobenzyl phthalate [MBzP], mono-2-ethylhexyl phthalate [MEHP] and MEHP%), motility (MBzP and MEHP) and INSL3 (MBzP, MEHP and MEHP%) (all p < 0.01). Higher seminal phthalate metabolite levels were associated with decreases in sperm concentration (MEHP and mono-2-ethyl-5-hydroxyhexyl phthalate), motility (mono-ethyl phthalate [MEP] and di-(2-ethylhexyl) phthalate [DEHP] metabolites), normal morphology (MEP), and INSL3 (monomethyl phthalate and MEP) (all p < 0.05). Our data suggest that INSL3 secretion, reproductive hormone balance, and sperm production and quality might be simultaneously adversely affected for individuals excreting increasing levels of phthalates metabolites (especially di-ethyl phthalate, butylbenzyl phthalate, and DEHP) in urine and semen samples.
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http://dx.doi.org/10.1016/j.chemosphere.2017.01.056DOI Listing
April 2017

Opposing prognostic roles of nuclear and cytoplasmic RACGAP1 expression in colorectal cancer patients.

Hum Pathol 2016 Jan 21;47(1):45-51. Epub 2015 Sep 21.

Department of Surgical Pathology, Changhua Christian Hospital, Changhua 50006, Taiwan; Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 35664, Taiwan; School of Medicine, Chung Shan Medical University, Taichung 40242, Taiwan. Electronic address:

Rac GTPase activating protein 1 (RACGAP1) plays a regulatory role in initiation of cytokinesis, control of cell growth and differentiation, and tumor malignancy, making it a potential prognostic biomarker. RACGAP1 is present in the nucleus, but a diffuse distribution in the cytoplasm also occurs. The aim of this study was to determine the impact of nuclear and cytoplasmic expression of RACGAP1 on clinical outcome to provide further evidence of a role in colorectal cancer. RACGAP1 expression was analyzed by immunohistochemistry in 166 cancer specimens from primary colorectal cancer patients. The mean follow-up time after surgery was 5.4 years (range, 0.01-13.10 years). The prognostic value of RACGAP1 on overall survival was validated by Kaplan-Meier analysis and Cox regression models. RACGAP1 is expressed in colorectal specimen and is present in both the nucleus and cytoplasm in different amounts. Colorectal cancer patients had opposite prognoses depending on the site of RACGAP1 expression. Patients with high nuclear RACGAP1 expression had poor outcomes, whereas those with high cytoplasmic RACGAP1 expression had favorable prognosis (P = .003 and P = .001, respectively). Patients with low nuclear but high cytoplasmic RACGAP1 expression had better survival compared with those with other combinations (P < .001). We suggest that RACGAP1 expression levels in the nucleus and cytoplasm, determined by immunohistochemical staining, predict opposite clinical outcomes and that both could be independent prognostic markers for colorectal cancer.
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http://dx.doi.org/10.1016/j.humpath.2015.09.002DOI Listing
January 2016

Phthalates might interfere with testicular function by reducing testosterone and insulin-like factor 3 levels.

Hum Reprod 2015 Nov 18;30(11):2658-70. Epub 2015 Sep 18.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan Research Center of Environmental Trace Toxic Substance, National Cheng Kung University, 138 Sheng-Li Road, Tainan 70403, Taiwan

Study Question: Do phthalates create a male reproductive hormone imbalance by down-regulating the secretion of testosterone and insulin-like factor 3 (INSL3)?

Summary Answer: Our study suggests that exposure to phthalates is related to a reduction in the secretion of testosterone and INSL3 in adult males.

What Is Known Already: There is evidence that exposure to phthalates, an abundant group of industrial plasticizers, negatively affects testosterone biosynthesis, but little is known about the mechanism in men. The hypothesis that exposure to phthalates reduces the levels of testosterone and INSL3, a marker of Leydig cell function, is underexplored.

Study Design, Size, Duration: This case-control study of 176 men ran from 2010 to 2012. Infertile men were recruited through infertility clinics in Taiwan, fertile men were recruited from childbirth preparation classes and all were categorized based on the World Health Organization definition of infertility and by the diagnoses of obstetricians.

Participants/materials, Setting, Methods: Urinary concentrations of 11 phthalate metabolites were measured, along with serum levels of FSH, LH, total testosterone (TT), estradiol, sex hormone-binding globulin and Inhibin B. Androgen status indices including free testosterone (fT) and the free androgen index (FAI) were calculated. The circulating INSL3 level was evaluated using a radioimmunoassay. Non-parametric analyses, trend tests and linear regression models were used.

Main Results And The Role Of Chance: Urinary mono-n-butyl phthalate (MnBP), mono-(2-ethylhexyl) phthalate (MEHP) and mono-2-ethyl-5-carboxypentyl phthalate were significantly higher in infertile than in fertile men. Serum Inhibin B, the Inhibin B : FSH ratio, the TT : LH ratio and INSL3 were significantly lower in infertile men. In multiple regression models controlled for potential confounders, there is an inverse association between urinary levels of mono-methyl phthalate (MMP), mono-iso-butyl phthalate (MiBP), MEHP, MEHP% and serum TT (P = 0.001, 0.007, 0.042 and 0.012, respectively). The inverse associations were also found between urinary levels of MiBP, monobenzyl phthalate (MBzP), MEHP, MEHP% and serum fT (P = 0.028, 0.017, 0.045 and 0.027, respectively); between urinary levels of MMP, MEHP, MEHP% and the TT : LH ratio (P = 0.004, 0.029 and 0.039, respectively); between urinary levels of MMP, MiBP, MnBP, MBzP, MEHP and the FAI (P = 0.002, 0.008, 0.037, 0.028, 0.042 and 0.016, respectively). Urinary MBzP and MEHP% were negatively associated with a decrease in serum INSL3 (P = 0.049 and <0.001). We also observed a strong inverse relationship between MEHP% quartiles and serum TT, fT, the TT : LH ratio and INSL3 (Ptrend = 0.003, 0.080, 0.002 and 0.012, respectively). Serum INSL3, TT, fT and the TT : LH ratio were lower for men in the highest MEHP% quartile than in the reference group (P = 0.007, 0.002, 0.090 and 0.001, respectively).

Limitations, Reasons For Caution: A potential limitation is using a single urine and blood sample to predict urinary phthalate metabolites and reproductive hormone status over long periods. However, there is evidence that a single measure provides a reliable result in population studies.

Wider Implications Of The Findings: Non-occupational exposure to phthalates, including di-2-ethylhexyl phthalate, might lead to adverse effects on testicular/Leydig cell function and be of concern owing to the ubiquitous multisource exposure to phthalates among the general population. Although our findings are in agreement with recent experimental data, more studies are required to draw firm conclusions on the relation of INSL3 to phthalate exposure or testicular/Leydig cell function.
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http://dx.doi.org/10.1093/humrep/dev225DOI Listing
November 2015

Null effect of ginsenoside Rb1 on improving glycemic status in men during a resistance training recovery.

J Int Soc Sports Nutr 2015 20;12:34. Epub 2015 Aug 20.

Department of Sports Sciences, Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan.

Background: Ginsenoside Rb1, a principle active ingredients of Panax ginseng, has been shown to lower blood glucose in animals and increase insulin secretion in cultured insulinoma cells. The aim of this study was to determine the effects of daily ginsenoside Rb1 supplementation on circulating glucose and insulin levels in men during a 5-day recovery period after an acute bout of resistance exercise.

Methods: Twelve gymnasts (20.5 ± 0.3 years of age) participated in this double blind placebo-controlled crossover trial. They were challenged by a lower-limb resistance exercise at a weight load of 85 % one-repetition maximal (1-RM) for 10 repetitions, six sets of the movement. Rb1 (1 ng/kg) or Placebo was orally delivered to participants daily during a 5-day recovery period after challenge. Circulating insulin, glucose and heart rate variability (HRV) were measured under fasted condition in the morning at Days 1, Day 3, and Day 5 during recovery.

Results: No significant effect of Rb1 on circulating glucose and insulin levels were found among participants during the 5-day recovery period. A persistent elevation in sympathetic nervous activity, indicated by increased HRV-low frequency/high frequency (HRV-LF/HF) power, during the Rb1 trial was observed.

Conclusions: The result of the study suggests that the null effect of Rb1 supplementation on lowering glucose and insulin levels of participants may be associated with chronic sympathetic activation.
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http://dx.doi.org/10.1186/s12970-015-0095-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545376PMC
March 2016

Effect of dehydroepiandrosterone administration on recovery from mix-type exercise training-induced muscle damage.

Eur J Appl Physiol 2013 Jan 16;113(1):99-107. Epub 2012 May 16.

Department of Kinesiology and Health Education, University of Texas at Austin, Austin, TX, USA.

This study aimed to determine the role of DHEA-S in coping against the exercise training mixing aerobic and resistance components. During 5-day successive exercise training, 16 young male participants (19.2 ± 1.2 years) received either a placebo (flour capsule) or DHEA (100 mg/day) in a double-blinded and placebo-controlled design. Oral DHEA supplementation significantly increased circulating DHEA-S by 2.5-fold, but a protracted drop (~35 %) was observed from Day 3 during training. In the Placebo group, only a minimal DHEA-S reduction (~17 %) was observed. Changes in testosterone followed a similar pattern as DHEA-S. Muscle soreness was elevated significantly on Day 2 for both groups to a similar extent. Lower muscle soreness was observed in the DHEA-supplemented group on Day 3 and Day 6. In the Placebo group, training increased circulating creatine kinase (CK) levels by approximately ninefold, while only a threefold increase was observed in the DHEA-supplemented group. This mix-type exercise training improved glucose tolerance in both groups, while lowering the insulin response to the glucose challenge, but no difference between treatments was observed. Our results suggest that DHEA-S may play a role in protecting skeletal muscle from exercise training-induced muscle damage.
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http://dx.doi.org/10.1007/s00421-012-2409-6DOI Listing
January 2013

Oral health of psychiatric inpatients: a survey of central Taiwan hospitals.

Gen Hosp Psychiatry 2011 May-Jun;33(3):253-9. Epub 2011 Apr 12.

Department of Psychiatry, Chang Bing Show Chwan Memorial Hospital, Lu-Kang, Taiwan.

Objective: The objective was to investigate the status of oral health and its determinants in a group of psychiatric inpatients in central Taiwan.

Method: A cross-sectional study of the oral health of psychiatric inpatients (n=200) in three hospitals in central Taiwan was carried out during a half-year period. Demographic data and data on oral health habits, dental visit frequency, treatment fear and dental health knowledge were collected. Oral health was determined by the Decayed/Missing/Filled Teeth (DMFT) index, Community Periodontal Index (CPI), Plaque Index and Gingival Index.

Results: In terms of prevalence of caries, the mean DMFT score for all patients was 14.9 ± 8.8 (S.D.), which was significantly worse than that in the general population. The CPI showed that only 10% of patients were periodontally healthy, 9.5% had bleeding, 31% had calculus and 49.5% had periodontal pockets. Increasing age, treatment anxiety, neglect of tooth-brushing and chronic ward inpatients were predictive factors for poor periodontal health. The self-awareness of poor oral health was inadequate and the treatment needs were huge in psychiatric inpatients.

Conclusion: The oral health of psychiatric inpatients was poor compared with the general population and was generally ignored by the patients themselves. The phenomenon is universal, occurring in both Western and Eastern countries.
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http://dx.doi.org/10.1016/j.genhosppsych.2011.03.001DOI Listing
September 2011

Effects of mixology courses and blood lead levels on dental caries among students.

Community Dent Oral Epidemiol 2010 Jun 26;38(3):222-7. Epub 2010 Mar 26.

Department of Environmental and Occupational Health, National Cheng Kung University, Tainan, Taiwan Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Miaoli, Taiwan Graduate Institute of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Institute of Environmental Health, College of Public Health, China Medical University and Hospital, Taichung, Taiwan School of Dentistry, China Medical University Hospital, Taichung, Taiwan Department of Baking Technology and Management, Kaoshiung Culinary College, Kaohsiung, Taiwan Faculty of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan.

Objective: Dental caries can be affected by alcohol consumption. Alcohol consumption also increases blood lead levels (BLLs) in humans and BLLs have been correlated with caries. Culinary students participate in mixology courses on either an elective or a mandatory basis. Therefore, we conducted this study to elucidate the effects of mixology courses and elevated BLLs on dental caries among students.

Methods: This study had a cross-sectional design. We recruited first-year at one hospitality college and one university in southern Taiwan in September 2004. We applied a questionnaire, collected a blood specimen and performed a dental caries examination for each student. The subjects comprised 133 students who had ever participated in a mixology course (≥2 credits) during high school (exposure group) and 160 who had not participated in such a course (control group).

Results: Compared with the control group, the exposure group had a higher prevalence of a DMFT index ≥ 0 (92.5% versus 81.2%, P = 0.005), a higher DMFT index [5.59 ± 3.53 (mean ± SD) versus 4.21 ± 3.64 teeth, P ≤ 0.001], and a higher BLL (3.12 ± 1.02 versus 2.67 ± 0.83 μg/dl, P = ≤ 0.001). After adjustment for potential confounders, dental caries was significantly associated with participation in a mixology course.

Conclusions:   Alcohol exposure associated with participation in a mixology course may have an effect on caries in students. These findings suggest that occupational safety and health education should be applied to students participating in mixology courses.
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http://dx.doi.org/10.1111/j.1600-0528.2009.00518.xDOI Listing
June 2010

Graft and diblock copolymer multifunctional micelles for cancer chemotherapy and imaging.

Biomaterials 2010 Mar 29;31(8):2293-301. Epub 2009 Dec 29.

Department of Chemical Engineering, National Tsing Hua University, Hsinchu, 300 Taiwan, ROC.

Multifunctional mixed micelles that constructed from poly(HEMA-co-histidine)-g-PLA and diblock copolymer PEG-PLA with functional moiety was developed in this study. The mixed micelles had well defined core shell structure which was evaluated by TEM. The functional inner core of poly(HEMA-co-histidine)-g-PLA exhibited pH stimulate to enable intracellular drug delivery and outer shell of PEG-b-PLA with functional moiety Cy5.5 for biodistribution diagnosis and folate for cancer specific targeting were synthesized at the end of the polymer chain. The graft and diblock copolymer self assembled to nanospheres against water with an average diameter below 120 nm without doxorubicin, and an average diameter of around 200 nm when loaded with drug. From drug released study, a change in pH destroy the inner core to lead a significant doxorubicin(Dox) release from mixed micelles. Cellular uptake of folate-micelles was found to be higher than that of non-folate-micelles due to the folate-binding effect on the cell membrane, thereby providing a similar cytotoxic effect to drug only against the HeLa cell line. In vivo study revealed that specific targeting of folate-micelles exhibited cancer targeting and efficiency expression on tumor growth, indicating that multifunctional micelles prepared from poly(HEA-co-histidine)-g-PLA and folate-PEG-PLA have great potential in cancer chemotherapy and diagnosis.
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http://dx.doi.org/10.1016/j.biomaterials.2009.11.059DOI Listing
March 2010

Effect of a two-month detraining on glucose tolerance and insulin sensitivity in athletes--link to adrenal steroid hormones.

Chin J Physiol 2006 Oct;49(5):251-7

Laboratory of Exercise Biochemistry, Taipei Physical Education College, Taipei 105, Taiwan, R.O.C.

Reduction in physical activity has been demonstrated to associate with the increased risk in insulin resistance and type 2 diabetes. To determine whether alteration in insulinemia, due to abstention from regular exercise training, is associated with changes in serum dehydroepiandrosterone sulfate (DHEA-S) and cortisol, 18 highly trained badminton players (21.2 +/- 0.3 years) were enrolled into a 2-month detraining study. Fasting serum insulin, glucose, DHEA-S, and cortisol were determined at trained state and at day 60 of detraining. Glucose tolerance and insulin sensitivity were assessed by an oral glucose tolerance test (OGTT). The 2-month detraining increased fasting glucose and insulin concentrations and body weight slightly, but did not significantly affect glucose tolerance and insulin response curve, in which 10 subjects had increased and 8 subjects had slightly decreased in the area under curve for insulin (IAUC). In the subjects with increased IAUC, serum cortisol was also elevated (from 0.44 +/- 0.07 to 0.83 +/- 0.26 U/l, P < 0.05) in parallel, and serum creatine kinase (CK) was unaltered during detraining. Whereas in the subjects with decreased IAUC, serum cortisol (from 0.51 +/- 0.19 to 0.54 +/- 0.14 U/l, no significance) was not changed and serum creatine kinase (from 461 +/- 179 to 151 +/- 21 U/l) was decreased during detraining. Two groups of detrained subjects exhibited a similar reduction in serum DHEA-S levels and slight elevation in body weight. The novel finding of the study is that the changes in serum cortisol, but not DHEA-S, were associated with the change in insulin sensitivity during early phase of lifestyle change from physically active to sedentary, and this response appears to be varied individually among athletes.
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October 2006

Glucose tolerance and insulin sensitivity following an one-week volleyball competition.

Chin J Physiol 2006 Jun;49(3):147-51

Laboratory of Exercise Biochemistry, Taipei Physical Education College, Taiwan, ROC.

The purpose of the study was to compare glucose tolerance and insulin sensitivity between trained (TR) and competition (CP) states, in relation to cortisol and testosterone levels. Sixteen highly trained volleyball players voluntarily participated in this study. The first testing session (TR state) occurred 1 week before the start of national level volleyball CP, and the second testing session (CP state) occurred next morning after the 1-week CP. Fasted serum sample was used for measuring cortisol and testosterone. Subjects were then orally challenged with 75 g of glucose solution for determinations of oral glucose tolerance test (OGTT) and insulin response. Under both fasted and glucose challenged conditions, glucose levels of CP were not different from TR state, whereas insulin levels of CP were significantly elevated above TR (50 min: from 78.8 +/- 8.7 to 96.6 +/- 8.1 microU/ml, P < 0.05; 80 min: from 62.8 +/- 7.0 to 82.0 +/- 7.3; P < 0.05). Muscle creatine kinase (CK) level in blood was significantly increased above TR, suggesting greater muscle damage by CP. Serum leptin level, percent fat mass, and body weight were not different between two states. CP significantly increased serum cortisol level without significantly change in testosterone level. The new finding of the study was that volleyball CP reduced the whole-body insulin sensitivity significantly compared to TR state. The greater level of insulin concentration under CP state appears to be associated with elevated serum cortisol level. Despites the benefit of increased physical activity on metabolic function is widely recognized, physiological stress associated with CP can result in attenuation of systemic insulin sensitivity compared TR state.
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June 2006

Glycogen overload by postexercise insulin administration abolished the exercise-induced increase in GLUT4 protein.

J Biomed Sci 2005 Dec 1;12(6):991-8. Epub 2005 Dec 1.

Center for General Education, National Chi-Nan University, Nantou, Taiwan, ROC.

To elucidate the role of muscle glycogen storage on regulation of GLUT4 protein expression and whole-body glucose tolerance, muscle glycogen level was manipulated by exercise and insulin administration. Sixty Sprague-Dawley rats were evenly separated into three groups: control (CON), immediately after exercise (EX0), and 16 h after exercise (EX16). Rats from each group were further divided into two groups: saline- and insulin-injected. The 2-day exercise protocol consisted of 2 bouts of 3-h swimming with 45-min rest for each day, which effectively depleted glycogen in both red gastrocnemius (RG) and plantaris muscles. EX0 rats were sacrificed immediately after the last bout of exercise on second day. CON and EX16 rats were intubated with 1 g/kg glucose solution following exercise and recovery for 16 h before muscle tissue collection. Insulin (0.5 microU/kg) or saline was injected daily at the time when glucose was intubated. Insulin injection elevated muscle glycogen levels substantially in both muscles above saline-injected group at CON and EX16. With previous day insulin injection, EX0 preserved greater amount of postexercise glycogen above their saline-injected control. In the saline-injected rats, EX16 significantly increased GLUT4 protein level above CON, concurrent with muscle glycogen supercompensation. Insulin injection for EX16 rats significantly enhanced muscle glycogen level above their saline-injected control, but the increases in muscle GLUT4 protein and whole-body glucose tolerance were attenuated. In conclusion, the new finding of the study was that glycogen overload by postexercise insulin administration significantly abolished the exercise-induced increases in GLUT4 protein and glucose tolerance.
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http://dx.doi.org/10.1007/s11373-005-9019-9DOI Listing
December 2005