农村妇女孕期全程拟除虫菊酯类农药暴露对子代早期发育影响的出生队列研究

Effects of pesticides on birth outcomes, growth, neurodevelopment of offspring has brought a great public concern. Because of lower toxicity of pyrethroids than other pesticides to human being, their application in agreculture and living environment has increased in amount year by year recently. The acute toxicity of pyrethroids has been cleared, however, their potential growth and neurodevelopmental toxicity have not been evaluated，especially, the relationship between exposure of pyrethroids in the whole period of gestination and birth outcome, growth and neurodevelopmental. This study proposes to follow pregnant women and their newborn children to explore the association between prenatal exposure to pyrethroids in low concentration and birth outcomes, neurodevelopment and hormone related to growth and development in the offspring. Conducted in rural Yunnan, which is one of most pyrethroids consume provinces, this study will recruit 500 pregnant women in an agriculture county, Yunnan, during their first trimester, and follow them each trimester. Their newborn children are also followed until their 1 year old. Pyrethroids exposure of pregnant women in each of their three trimester and fetus will be measured using pyrethroids metabolites including cis- isomers of 2,2-dichlorovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (cis-DCCA), trans-isomers of 2,2-dichlorovinyl-2,2-dimethylcyclopropane-1-carboxylic acid （trans-DCCA）, 3-phenoxybenzoic acid (3-PBA), cis-2,2dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (cis-DBCA), 4-fluoro-3-phenoxybenzoic acid(4F3PBA) in urine of pregnant women, meconium and urine of infants. Meanwihile, a questionnare will be used to get information on diet and exposure to tobacco smoke, and potential confounders once an each trimester of pregnant women. The outcome varibles of interest-fetal growth and development: birth weight, height, head circumference, hormone indicators in umbilical cord blood (FT3, FT4, TSH, GH, IGF-1) and Baleys scores. The hormones will be measured using radioimmunoassay (RIA). Baleys scores for newborn infants at their 1 month, 6 months and 12 months of age will be evaluated by Baleys Scale of infants development Ⅲ (BSID-Ⅲ). Infant exposure of pyrethroids will be measured by pyrethroids metabolites mentioned above in their urine when infants are 6 months and 12 months of age, respectively. The pyrethroids metabolites will be determined by Ultra-performance Liquid Chromatography Couple with Tandem Mass Spectrometer （UHPLC-MS/MS）. The Structural Equation Modeling (SEM) with Markov Chain Monte Carlo (MCMC) Stochastic Simulation Method will be used to reveal and quantify the complex causal relationship between pyrethroids exposure of maternal and offspring's growth and neurodevelopment effects. Findings will be used to supply reference to make an appropriate policy for reasonable utilization of pyrethroids under the guarantee to offspring health.

农药对子代的影响受到社会广泛关注。近年来因拟除虫菊酯类农药对人体相对低毒，广泛用于农业生产和生活环境杀虫。国内外以往研究妇女孕期长期低剂量暴露对妊娠结局、婴儿体格和神经系统的影响无一致结论，中国也缺乏系统研究。本研究在农村自妇女孕早期起建立出生队列500对，观察至小儿1岁；超高效液相色谱串联质谱法检测拟除虫菊酯农药代谢产物cis/trans-DCCA、3-PBA、DBCA和4F3PBA在妇女不同孕期尿液和新生儿胎便中水平，以评估不同孕期、孕全程和胎儿暴露状况；观察妊娠结局、测量脐血FT3、FT4、TSH、生长激素、胰岛素样生长因子-1；婴儿1月、6月和1岁时，用贝利婴幼儿发育量表Ⅲ测评其神经心理行为发育状况；采用结构方程模型，通过马尔科夫链-蒙特卡洛随机模拟迭代方法，定量化孕期农药暴露对子代早期发育效应多变量间的复杂因果关联。研究结果为农药合理使用与保障儿童健康之间的相互平衡提供科学依据。

本研究聚焦农药暴露农药暴露对健康影响的热点问题，在云南宣威农村自妇女孕早期起建立出生队列807对，观察至儿童1岁。结果发现：.1. 妇女孕期PYRs代谢产物3-PBA、4F3PBA和DBCA检出率在48.97%-81.95%，以3-PBA最高，检出量中位数在0.265-0.716μg/ml。81.61%胎便中检出3-PBA，孕三期妇女尿液与胎便PYRs代谢产物无相关。婴儿6月和1岁3-PBA、4F3PBA和DBCA检出率在25.16%-90.32%，检出量中位数在0.000-0.278μg/ml。婴儿尿样PYRs代谢产物检出率高于孕期；1岁儿童3-PBA、DBCA检出率和检出量平均较6月婴儿高。孕期继续做农活，家离农田近及孕期使用家用杀虫剂是影响孕中晚期暴露的主要危险因素，孕早期丈夫文化程度和收入高的家庭、孕妇蔬菜食用频率高，均可增加PYRs暴露风险。.2. 孕晚期4F3PBA可增加不良出生结局风险，未发现各孕期PYRs代谢产物与脐血FT3、TSH、IGH-1相关，但孕期PYRs暴露可促进FT4和GH分泌。孕三期DBCA与新生儿出生体重和头围正相关。未发现孕期和婴儿PYRs代谢产物与儿童体重和身长有关。在孕期PYRs代谢产物与BayleyⅢ五个维度得分分布滞后非线性模型分析中，孕晚期DBCA可降低6月婴儿语言得分，孕中期和6月婴儿4F3PBA可降低1岁儿童运动发育得分，但孕期及儿童3-PBA与婴儿神经心理发育无关联。相对于<P75, 孕早期PYRs代谢产物合计（∑PYRs）≧P75与儿童认知和运动发育呈负相关，孕中期∑PYRs≧P75与儿童认知、语言发育呈负相关。.综上，妇女孕全程和婴儿PYRs普遍暴露，但总体暴露水平低于多数国内外报道。孕期PYRs暴露与胎儿累积暴露无相关。非直接接触农药的田间劳动以及摄入蔬菜可增加农药暴露风险，以4F3PBA为主要代谢产物农药可增加不良出生结局风险。农村妇女日常生产生活环境PYRs暴露对子代早期发育多个方面有影响，且较高浓度PYRs暴露可抑制婴儿神经心理发育。研究提示，妇女孕期要尽量减少PYRs暴露，减少田间劳动，避免直接接触农药和家用杀虫剂，尤其是以4F3PBA为主要代谢产物的PYRs。本研究为继续追踪观察孕期PYRs暴露对子代发育的中远期影响奠定了基础。

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