STUDY QUESTION Is there a possible association between prenatal phthalate exposure and late effects in teenage daughters with respect to reproductive hormone levels, uterine volume, and number of ovarian follicles? SUMMARY ANSWER Our study showed subtle associations between phthalate metabolite concentrations in maternal serum from pregnancy or cord blood and LH and insulin-like growth factor 1 (IGF-1) levels as well as uterine volume in their daughters 16 years later. WHAT IS KNOWN ALREADY Endocrine-disrupting environmental chemicals may adversely affect human reproductive health, and many societies have experienced a trend toward earlier puberty and an increasing prevalence of infertility in young couples. The scientific evidence of adverse effects of foetal exposure to a large range of chemicals, including phthalates, on male reproductive health is growing, but very few studies have explored effects on female reproduction. STUDY DESIGN, SIZE, DURATION This follow-up study included 317 teenage daughters who were part of the Copenhagen Mother–Child Cohort, a population-based longitudinal birth cohort of 1210 females born between 1997 and 2002. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 317 female participants (median age 16 years) were examined for weight, height, and menstrual pattern. A serum sample was analysed for concentrations of reproductive hormones, and trans-abdominal 3D ultrasonography was performed to obtain the number of ovarian follicles, ovarian and uterine size. Prenatal maternal serum samples were available for 115 females, and cord blood samples were available for 118 females. These were analysed for concentrations of 32 phthalate metabolites. Weighted quantile sum regression was used for modelling associations of combined prenatal phthalate exposure with the reproductive outcomes in post-menarcheal females. MAIN RESULTS AND THE ROLE OF CHANCE In bivariate correlation analyses, negative significant associations were found between several prenatal phthalate metabolite concentrations and serum hormone concentrations (testosterone, 17-OH-progesterone, and IGF-1) as well as number of ovarian follicles in puberty. Positive significant correlations were found between prenatal phthalate exposure and FSH and sex hormone-binding globulin concentrations. Combined analyses of phthalate exposure (weighted quantile sums) showed significant negative associations with IGF-1 concentration and uterine volume as well as a significant positive association with LH concentration. LIMITATIONS, REASONS FOR CAUTION Phthalate metabolites were measured in serum from single prenatal maternal blood samples and cord blood samples. Potential concomitant exposure to other endocrine-disrupting environmental chemicals before or after birth was not controlled for. The study population size was limited. WIDER IMPLICATIONS OF THE FINDINGS Our results support the need for further research into possible adverse effects of environmental chemicals during foetal development of the female reproductive system. STUDY FUNDING/COMPETING INTEREST(S) The work was supported by The Center on Endocrine Disruptors (CeHoS) under The Danish Environmental Protection Agency and The Ministry of Environment and Food (grant number: MST-621-00 065). No conflicts of interest are declared. TRIAL REGISTRATION NUMBER N/A.

中文翻译：

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16 岁女儿产前邻苯二甲酸酯暴露和青春期发育：生殖激素和卵巢卵泡数量


研究问题 产前邻苯二甲酸酯暴露与十几岁女儿的生殖激素水平、子宫体积和卵巢卵泡数量方面的迟发效应之间是否存在可能的关联？摘要答案 我们的研究表明，妊娠或脐带血和 LH 中母体血清中的邻苯二甲酸酯代谢物浓度与 16 年后女儿的胰岛素样生长因子 1 （IGF-1） 水平以及子宫体积之间存在微妙的关联。已知的 内分泌干扰环境化学物质可能会对人类生殖健康产生不利影响，许多社会都经历了青春期提前和年轻夫妇不孕症患病率增加的趋势。胎儿接触包括邻苯二甲酸盐在内的多种化学物质对男性生殖健康有不利影响的科学证据越来越多，但很少有研究探讨对女性生殖的影响。研究设计、规模、持续时间 这项后续研究包括 317 名十几岁的女儿，她们是哥本哈根母子队列的一部分，这是一个基于人群的纵向出生队列，由 1210 年至 1997 年间出生的 2002 名女性组成。参与者/材料、设置、方法 共对 317 名女性参与者 （中位年龄 16 岁） 进行了体重、身高和月经模式的检查。分析血清样本的生殖激素浓度，并进行经腹 3D 超声检查以获得卵巢卵泡的数量、卵巢和子宫大小。有 115 名女性的产前母体血清样本，118 名女性的脐带血样本。分析了 32 种邻苯二甲酸酯代谢物的浓度。 加权分位数和回归用于模拟产前邻苯二甲酸酯联合暴露与月经后女性生殖结局的关联。主要结果和机会的作用 在双变量相关性分析中，发现几种产前邻苯二甲酸酯代谢物浓度与血清激素浓度（睾酮、17-OH-孕酮和 IGF-1）以及青春期卵巢卵泡数量之间存在负显著关联。发现产前邻苯二甲酸酯暴露与 FSH 和性激素结合球蛋白浓度之间存在显著正相关。邻苯二甲酸酯暴露 （加权分位数和） 的综合分析显示与 IGF-1 浓度和子宫体积呈显著负相关，与 LH 浓度呈显著正相关。局限性，谨慎的原因 在单胎产前母体血样和脐带血样本的血清中测量邻苯二甲酸酯代谢物。出生前或出生后可能伴随暴露于其他内分泌干扰环境化学物质的情况未得到控制。研究人群规模有限。研究结果的更广泛影响 我们的结果支持需要进一步研究环境化学物质在女性生殖系统胎儿发育过程中可能产生的不利影响。研究资金/竞争利益 这项工作得到了丹麦环境保护署下属的内分泌干扰物中心 （CeHoS） 和环境与食品部（资助号：MST-621-00 065）的支持。没有声明利益冲突。试验注册号 N/A。