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Exposure to bisphenol A during infancy including perinatal period and their association with oxidative stress
주산기를 포함한 영유아기의 BPA 노출 및 산화 손상과의 상관성

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Authors
이장우
Advisor
김성균
Major
보건대학원 환경보건학과
Issue Date
2018-08
Publisher
서울대학교 대학원
Description
학위논문 (박사)-- 서울대학교 대학원 : 보건대학원 환경보건학과, 2018. 8. 김성균.
Abstract
Bisphenol A (BPA) is a chemical widely used in numerous consumer products, including baby bottles, reusable water bottles, food container, stretch films, papers, and cardboard. Therefore, BPA has been detected in a variety of environmental samples (i.e., water, air, and dust), foods samples (i.e., plastic container and can linings), and biological samples (i.e., serum, urine, placenta, breast milk, and amniotic fluid). The animal and human studies suggested that BPA could exhibit other modes of endocrine disruption such as androgen, glucocorticoid receptors etc. in addition to binding to estrogen receptors, and results in changes in tissue enzymes and hormone receptors. In addition, BPA can disturb oxidative homeostasis through the direct or indirect pathway, including mitochondrial function, modulation of antioxidant enzymes in the brain, kidney, and testis.

Fetuses and infants can be biologically more sensitive to the same toxicant exposure on a body weight basis than adults. However, a few epidemiological studies assessed the relationship between exposure to BPA and oxidative stress in women and adults and the information on the BPA exposure levels of fetuses and infants is still limited. Therefore, it is necessary to investigate the BPA exposure and health effects in this susceptible population. In order to address these issues, data on infant BPA exposure and health effect biomarkers in the CHECK study were used. The CHECK study (Childrens Health and Environmental Chemicals in Korea) is designed to collect information related to exposure of environmental pollutants (POPs, BPA, Phthalates and heavy metals) during pregnancy and early childhood.

In CHECK study, Pregnant women and their matching infants were recruited from six university hospitals located in four cites of Korea in 2011-2013 (n = 335). For this study, the biological samples (serum, urine, placenta, breast milk, cord serum and neonatal urine) were collected from pregnant women and their babies (n = 318) and then infants urine (n = 187) and baby food (n = 210) samples were also collected at 9, 12, and 15 months after birth from follow up panel (n = 173). The urine samples (n=271) in the study of association with oxidative stress comprised 190 infants for whom urinary BPA levels, oxidative stress marker levels, and covariate data were available. BPA levels in the biological and food samples were determined with HPLC-MS/MS and GC-MS, respectively. The urinary free cortisol level was analyzed at Samkwang Medical Laboratories and 8OHdG (8-hydroxy-2-deoxyguanosine) level was measured using an EIA kit and spectrophotometer.

This study was designed based on the following objectives. The specific objectives of this study were (1) to describe the perinatal BPA exposure using correlations and concentration ratios in mother-neonate paired samples, (2) to assess the BPA exposure of the weaning period through the contamination status in urine and baby food samples, (3) to estimate the health effect on BPA exposure by the correlation between BPA levels and oxidative stress markers in repeatedly collected urine samples.



In chapter II, BPA exposure levels in various body fluids and tissues of pregnant women were determined and fetus and infant exposures to BPA based on associations between mother and their neonate's samples and BPA ratios in mother–neonate paired samples could be described. The median BPA concentration in the samples decreased in the order of neonatal urine (4.75 ng/mL), maternal urine (2.86 ng/mL), cord serum (1.71 ng/mL), maternal serum (1.56 ng/mL), breast milk (0.74 ng/mL), and the placenta (0.53 ng/g). In comparison with other studies, BPA concentration was higher in maternal and neonatal urine but similar in the other samples. There were only significant correlations between maternal urine and cord serum, maternal urine, and placenta. We estimated the ratios of BPA levels in the other sample types to those in maternal serum. The median (95th percentile) cord serum-to-maternal serum ratio was 1.12 (15.2) for mother–fetal pairs (n=160), in which BPA was detected in both matrices. The placenta-, maternal urine-, neonatal urine-, and breast milk-to-maternal serum ratios were 0.28 (5.31), 1.79 (29.9), 1.98 (28.2), and 0.51 (10.5), respectively. In addition, the 95th percentile values were 14–20-fold greater than the medians. The detection of BPA in cord serum and neonatal urine indicated that fetuses were exposed to BPA via the mother. These variations of BPA ratios suggest that pregnant women are exposed to BPA repeatedly and persistently and that infants could encounter high BPA exposure via placental transfer and breastfeeding.



In chapter III, the BPA levels in baby food and urine of infants were investigated at 9, 12, and 15 months after birth. Median (IQR, interquartile range) levels of BPA were 0.45 ng/g (IQR: N.D (No Detection) -5.16 ng/g wet weight) in homemade baby-food and 0.93 µg/L (IQR:


In chapter IV, BPA, 8-OHdG and free cortisol levels in repeatedly collected urine samples of infants were examined, and then the correlations between urinary BPA and oxidative stress markers with repeated measures for each individual were estimated. The specific-gravity corrected geometric mean (geometric standard deviation) of all urine samples was 1.9 (4.9) ng/mL (median and 95th percentile: 0.8 and 27.5 ng/mL), and those of 8-OHdG and free cortisol were 63.7 (2.2) ng/mL (median and 95thpercentile: 61.0 and 282 ng/mL), 15.6 (2.6) µg/dL (median and 95thpercentile: 16.7 and 66.8 µg/dL), respectively. The BPA was significantly associated with both 8-OHdG and free cortisol with non-linear relationships (p<.0001). The BPA levels were categorized in low, medium, and high group with 25th and 75th percentile, and then the effect of BPA exposure on 8-OHdG and free cortisol using linear mixed effect model after adjustment for infant gender, age, and other chemical levels [phthalate metabolites, lead (Pb) and mercury (Hg)]. BPA was not associated with free cortisol. In the associations of BPA levels with 8-OHdG, the MnBP was also found to interact strongly with BPA exposure. In a high group of MnBP, 8-OHdG levels of a high group of BPA was higher than those of low and medium groups. Therefore, exposure to both compounds affects the urinary 8-OHdG. These results were supported by prior studies that reported the association between BPA exposure and 8-OHdG, although previous associations were found in pregnant women, adults. In addition, the free cortisol levels were significantly correlated with 8-OHdG levels (ρ=0.42, p<.0001), indicating a high linking of them on the pathway. Our results suggest the possible oxidative stress of BPA during important prenatal and postnatal periods of development.



In conclusion, this study has established that the current levels of exposure to BPA could be associated with the oxidative stress during infancy. Compared with other studies, the BPA in umbilical cord blood and neonatal urine were high and infant urine was similar. The variations of BPA ratios indicate individual differences in the amounts of BPA delivered from mother to fetus due to differences in life patterns and metabolic function of mothers. BPA in food did not show significant correlation with urinary BPA which suggested there was another source of exposure in environments and behavior of infants. In addition, positive associations of the BPA exposure on 8-OHdG were found, but not free cortisol. These results implied that prenatal and postnatal BPA exposure could induce oxidative stress in fetuses and infants. Therefore, considering the effects of BPA exposure on oxidative stress during gestation and early life stages, further studies are needed to identify the BPA exposure sources of pregnant women and infants through continuous BPA monitoring and to identify the mechanisms of action for BPA on oxidative stress with health implications.



Keywords: Bisphenol A, neonates and infants, BPA ratio, urine, homemade baby-food, oxidative stress, 8-OHdG, free cortisol
Language
English
URI
https://hdl.handle.net/10371/143120
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Graduate School of Public Health (보건대학원)Dept. of Environmental Health (환경보건학과)Theses (Ph.D. / Sc.D._환경보건학과)
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