The study on the association between phthalate exposure with early onset of girl puberty and intervention strategy development

• Main Authors: Chung-YuChen, 陳重羽
• Other Authors: Ching-Chang Lee
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/26ggg5

博士 === 國立成功大學 === 環境醫學研究所 === 103 === Girls are maturing earlier than in past decades and the amount of phthalates used in consumer products has concurrently risen. The hypothesis that exposure to phthalates may disturb kisspeptin secretion and thereby cause early-onset puberty is unexplored. Is there an association between exposure to phthalates and the timing of female puberty? In part I, a case-control study ran from 2006 to 2009. We enrolled 104 girls. Girls in the central precocious puberty (CPP) (case) group were recruited from a pediatric endocrinology policlinic in Taiwan, prepubescent controls were recruited from local elementary schools and kindergartens, and all were categorized based on a pediatrician's diagnosis. The physical characteristics of puberty were assessed and levels of LH, FSH, estradiol and kisspeptin-54 in blood samples were evaluated using radioimmunoassay. Reversed-phase high-performance liquid chromatography-tandem mass spectrometry was used to analyze seven urinary phthalate metabolites. Nonparametric analyses, trend tests, and linear regressions were performed on the data. Seven urinary phthalate metabolites in the CPP group were significantly (p 〈 0.05) higher than in prepubescent controls. Serum kisspeptin-54 levels were higher (p = 0.022) in the CPP group than controls and were still significantly higher after adjusting for age (p = 0.03). There was a significant increasing trend (ptrend = 0.005) between levels of kisspeptin and the stages of puberty. The concentration of kisspeptin-54 did not change in girls treated with gonadotropin-releasing hormone agonist. There was a significant positive correlation between kisspeptin-54 and urinary mono-n-butyl phthalate (MBP) (ng/ml: R2 = 0.251, p 〈 0.001; ug/g-creatinine: R2 = 0.109, p = 0.024). In part II, children in Taiwan seem to be exposed higher concentrations of phthalates than do children in Western countries. We developed intervention strategies to reduce the exposure of phthalates in Taiwanese girls. Thirty girls 4-13 years old who had been exposed to high levels of phthalates were selected from prior studies. To reduce their phthalate-exposure sources, we developed seven intervention strategies: handwashing, not using plastic containers, not eating food with a plastic bag/plastic-wrap cover, not microwaving food, not taking nutrition supplements, and reducing use of cosmetics/personal care products. Pre- and post-intervention urine samples were collected during a one-week study. HPLC-MS/MS was used to analyze urinary phthalate metabolites. The dominant urinary phthalate metabolite was MBP, followed by mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5 -carboxypentyl) phthalate (MECPP). Post-intervention concentrations of eight urinary phthalate metabolites were significantly lower. Girls in the high-frequency handwashing group had significantly lower urinary MBP (p = 0.009) and mono-methyl phthalate (MMP) (p = 0.07) than did girls in the low-frequency handwashing group. Girls who drank fewer beverages from plastic cups had significantly lower urinary MBP (p = 0.016), MEHHP (p = 0.038), and MECPP (p = 0.012). Girls who used less shampoo and shower gel also had marginally significantly lower urinary MBP (p = 0.06) and mono-ethyl phthalate (MEP) (p = 0.06). Kisspeptin may promote the onset of puberty in girls exposed to a high level of phthalates. The increasing body burden of phthalate metabolites is positively correlated with the rising level of kisspeptin. We also found that kisspeptin was not suppressed, even when the participant was treated with gonadotropin-releasing hormone agonist. Developing a kisspeptin antagonist might be another strategy for treating precocious puberty. Our study suggests that exposure to di-n-butyl phthalate (DBP) may increase kisspeptin secretion and promote the early onset of puberty. The intervention strategies that we set up in this study were effective for reducing exposure to phthalates in children. Handwashing and drinking fewer beverages from plastic cups were the most effective strategies for reducing phthalate metabolites in urine, especially MBP and di(2-ethylhexyl) phthalate (DEHP) metabolites. Education and voluntary self-restraint were useful for reducing the body burden of phthalates.