BACKGROUND Per- and polyfluoroalkyl substances (PFAS), endocrine disrupting chemicals with worldwide exposure, cause changes in mammary gland development in rodents. A few human studies report delay in pubertal events with increasing perfluorooctanoic acid (PFOA) exposure, but to our knowledge none have examined reproductive hormone levels at thelarche. METHODS In a cohort of Greater Cincinnati (GC) and San Francisco Bay Area (SFBA) girls recruited at 6-8 years of age, clinical examinations were conducted annually or semiannually with sequential Tanner staging. PFAS concentrations were measured in the first serum sample of 704 girls. In 304 GC girls, estradiol (E2), estrone (E1), testosterone (T), and dihydroepiandrosterone sulfate (DHEAS) were measured in serum at four time points around puberty. Relationships between PFAS and age at thelarche, pubarche, and menarche were analyzed using survival and structural equation models. The association between PFAS and reproductive hormones was assessed using linear regression models. RESULTS Median PFOA serum concentrations in GC (N=353, 7.3 ng/mL) and the SFBA (N=351, 5.8 ng/mL) were higher than in the U.S. POPULATION In multivariable Cox proportional hazard models [adjusted for race, body mass index (BMI)], increasing serum log-transformed PFOA was associated with a delay in pubarche [hazard ratio (HR)=0.83; 95% CI: 0.70, 0.99] and menarche (HR=0.04; 95% CI: 0.01, 0.25). Structural equation models indicated a triangular relationship between PFOA, BMI percentile, and the age at the pubertal milestone. Increased PFOA had a statistically significant direct effect of delay on all three milestones, as did BMI. Perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDeA), and 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (Me-PFOSA-AcOH) also were associated with later thelarche, and Me-PFOSA-AcOH also with later pubarche. PFOA was inversely associated with DHEAS (p<0.01), E1 (p=0.04), and T (p=0.03) concentrations at 6 months prior to puberty. CONCLUSIONS PFAS may delay pubertal onset through the intervening effects on BMI and reproductive hormones. The decreases in DHEAS and E1 associated with PFOA represent biological biomarkers of effect consistent with the delay in onset of puberty. https://doi.org/10.1289/EHP11811.

中文翻译：

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对大辛辛那提和旧金山湾区年轻女孩的纵向研究显示，接触全氟烷基物质以及与青春期开始和血清生殖激素的关系。

背景技术全氟烷基物质和多氟烷基物质（PFAS）是一种全球范围内暴露的内分泌干扰化学物质，会导致啮齿类动物乳腺发育发生变化。一些人类研究报告称，随着全氟辛酸 (PFOA) 暴露的增加，青春期事件会延迟，但据我们所知，没有一项研究检查了乳房发育时的生殖激素水平。方法 在大辛辛那提 (GC) 和旧金山湾区 (SFBA) 招募的 6-8 岁女孩队列中，每年或每半年进行一次临床检查，并进行连续的 Tanner 分期。对 704 名女孩的第一份血清样本中的 PFAS 浓度进行了测量。在 304 名 GC 女孩中，在青春期前后的四个时间点测量了血清中的雌二醇 (E2)、雌酮 (E1)、睾酮 (T) 和硫酸二氢表雄酮 (DHEAS)。使用生存和结构方程模型分析 PFAS 与乳房初发育、阴毛初潮和初潮年龄之间的关系。使用线性回归模型评估 PFAS 和生殖激素之间的关联。结果 GC 中的 PFOA 血清浓度中位数（N=353，7.3 ng/mL）和 SFBA（N=351，5.8 ng/mL）高于美国人群 在多变量 Cox 比例风险模型中 [根据种族、体重进行调整]指数（BMI）]，血清对数转换 PFOA 的增加与阴毛初露延迟相关[风险比（HR）= 0.83；95% CI: 0.70, 0.99] 和初潮 (HR=0.04; 95% CI: 0.01, 0.25)。结构方程模型表明 PFOA、BMI 百分位和青春期里程碑年龄之间存在三角关系。PFOA 的增加对所有三个里程碑的延迟都有统计学上显着的直接影响，BMI 也是如此。全氟壬酸 (PFNA)、全氟癸酸 (PFDeA) 和 2-(N-甲基-全氟辛烷磺酰氨基) 乙酸 (Me-PFOSA-AcOH) 也与晚期乳房发育有关，而 Me-PFOSA-AcOH 也与晚期阴毛初露有关。PFOA 与青春期前 6 个月时的 DHEAS (p<0.01)、E1 (p=0.04) 和 T (p=0.03) 浓度呈负相关。结论 PFAS 可能通过对 BMI 和生殖激素的干预作用来延迟青春期的开始。与 PFOA 相关的 DHEAS 和 E1 降低代表了与青春期开始延迟一致的生物学生物标志物。https://doi.org/10.1289/EHP11811。