BACKGROUND Organophosphate esters (OPEs) are a class of alternative replacements for polybrominated diphenyl ethers. In vitro and in vivo studies suggested that OPEs may disrupt the homeostasis of sex steroid hormones. However, human evidence in children and adolescents is limited. OBJECTIVES We conducted a cross-sectional analysis of the associations between OPE biomarkers and sex steroid hormones among children (6-11 years) and adolescents (12-19 years) in the U.S. National Health and Nutrition Examination Survey, 2013-2014. METHODS Participants aged 6-19 years who had available data on urinary OPE metabolites, serum sex hormones [total testosterone (TT), estradiol (E2)] and sex hormone binding globulin (SHBG) were included (n = 544). Free androgen index (FAI) calculated as TT divided by SHBG and a ratio of TT to E2 (TT/E2) were generated. Five urinary OPE metabolites were examined. A constructed puberty status was defined as either high steroid hormone levels (TT ≥ 50 ng/dL in males and E2 ≥ 20 pg/ml in females) or onset of menarche. Multiple linear regression and weighted quantile sum (WQS) regression analyses stratified by sex-age and sex-puberty-status groups were conducted to examine the associations of OPE metabolites and its mixture with sex hormone levels. RESULTS After adjusting for covariates, dibutyl phosphate (DBUP) and dibutyl phosphate (DPHP) were significantly inversely associated with TT (or FAI) and E2; DBUP was negatively associated with SHBG; and DPHP was positively associated with SHBG and TT/E2 in female adolescents. In male adolescents, we observed monotonic negative associations of bis(1,3-dichloro-2-propyl) phosphate (BDCPP), DBUP or DPHP with TT (or FAI) and E2, and positive associations of BDCPP and DPHP with SHBG. Among adolescents, the OPEs index was negatively associated with TT [WQS beta = -0.29 (95% confidence interval: -0.51, -0.07) in males and -0.15 (-0.28, -0.01) in females ], FAI [-0.46 (-0.71, -0.2) in males and -0.23 (-0.41, -0.05) in females] and E2 [-0.25 (-0.41, -0.1) in males and -0.33 (-0.59, -0.08) in females], with stronger associations with TT and FAI in males and a slightly stronger association with E2 in females. In addition, the OPEs index presented a comparable positive association with SHBG in both sexes of adolescents. In contrast, significant associations of individual OPE metabolites or OPEs index with sex hormones were sparse in children. Results by sex-puberty status in single pollutant and WQS regression analyses presented a similar pattern, where most of the significant associations were limited to the pubertal individuals. Of note, stronger inverse associations of the OPEs index with TT and FAI remained in pubertal boys. But the association between the OPEs index and E2 was non-significant in pubertal girls, and only in pubertal boys did the OPEs index show a significant and stronger inverse association with E2. CONCLUSIONS Exposure to OPEs, either individually or as a mixture, was associated with decreased levels of certain sex steroid hormones (TT, FAI, and E2) and increased levels of SHBG in adolescents or pubertal individuals, with the associations presenting somewhat sex-dependent pattern. However, there is little evidence of the significant associations in children or prepubescent ones. Given the cross-sectional nature of the analysis, our findings need further confirmation.

中文翻译：

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NHANES 2013-2014年6-19岁儿童和青少年中有机磷酸酯与性激素之间的关联。

背景技术有机磷酸酯（OPE）是多溴代二苯醚的一类替代替代品。体外和体内研究表明，OPE可能会破坏性类固醇激素的体内稳态。但是，儿童和青少年的人类证据有限。目的我们在2013-2014年美国国家健康和营养调查中对儿童（6-11岁）和青少年（12-19岁）中的OPE生物标志物与性类固醇激素之间的关联进行了横断面分析。方法包括6-19岁的参与者，这些参与者具有尿OPE代谢产物，血清性激素[总睾丸激素（TT），雌二醇（E2）]和性激素结合球蛋白（SHBG）的数据（n = 544）。生成了以TT除以SHBG得出的游离雄激素指数（FAI），以及TT与E2的比率（TT / E2）。检查了五种尿OPE代谢物。公认的青春期状态定义为高类固醇激素水平（男性TT≥50 ng / dL，女性E2≥20 pg / ml）或初潮发作。按性别，性别和青春期状态分层，进行了多元线性回归和加权分位数和（WQS）回归分析，以检验OPE代谢产物及其混合物与性激素水平之间的关系。结果在调整协变量后，磷酸二丁酯（DBUP）和磷酸二丁酯（DPHP）与TT（或FAI）和E2呈显着负相关。DBUP与SHBG负相关；DPHP与女性青少年SHBG和TT / E2呈正相关。在男性青少年中，我们观察到磷酸双（1,3-二氯-2-丙基）（BDCPP）单调负相关，DBUP或DPHP与TT（或FAI）和E2，以及BDCPP和DPHP与SHBG的正相关。在青少年中，OPEs指数与TT呈负相关[男性，WQS beta = -0.29（95％置信区间：-0.51，-0.07），女性--0.15（-0.28，-0.01）]，FAI [-0.46（男性为-0.71，-0.2），女性为-0.23（-0.41，-0.05）]和E2 [男性为-0.25（-0.41，-0.1），女性为-0.33（-0.59，-0.08）]，男性与TT和FAI的关联更强，女性与E2的关联更强。此外，在两个性别的青少年中，OPEs指数均与SHBG具有可比的正相关。相比之下，儿童中个别OPE代谢物或OPEs指数与性激素的显着相关性稀疏。单一污染物的性别-青春期状态和WQS回归分析得出的结果呈现出相似的模式，其中大多数重要关联仅限于青春期个体。值得注意的是，青春期男孩中OPEs指数与TT和FAI的反向关联更强。但是，在青春期女孩中OPEs指数与E2之间的关联不显着，只有在青春期男孩中，OPEs指数才显示出与E2显着且更强的逆向关联。结论单独或混合使用OPE与青少年或青春期个体中某些性类固醇激素（TT，FAI和E2）的水平降低以及SHBG的水平升高有关，并且这种关联呈现出性别依赖性。然而，几乎没有证据表明儿童或青春期前有明显的关联。考虑到分析的横截面性质，我们的发现需要进一步确认。