Аннотация:Aim: We examined the association of prepubertal urinary phthalate metabolites with age at pubertal onset in a prospective cohort of Russian boys. Methods: 516 boys were enrolled at ages 8-9 years (2003-2005). A single physician performed annual physical exams including Tanner Staging (genitalia (G), pubarche (P)) and testicular volume (TV) by orchidometer, and parents/guardians completed medical history and demographic questionnaires. Annual spot urines were collected, and each boy’s prepubertal urines were pooled. 15 phthalate metabolite concentrations including anti-androgenic monobenzyl (MBzP), mono-n-butyl (MnBP), mono-isobutyl (MiBP), and metabolites of di(2-ethylhexyl) (DEHP) and di-isononyl (DiNP) were measured with HPLC-MS/MS and isotope dilution quantification at Moscow State University. We calculated the molar sum of DEHP and DiNP metabolites. Interval-censored models were used to assess associations of quartiles of individual and summed metabolites with pubertal onset indicators -- G2, P2 and TV >3mL -- adjusted for covariates and specific gravity. Results: 320 boys (62%) had ≥1 prepubertal urine samples (range:1-6; median=3). Median concentrations of MBzP, MnBP, and MiBP were 6.0, 194, and 57 ng/mL, respectively. In adjusted models, the highest versus lowest quartile of MBzP was associated with later pubertal onset, by 6.5 months (95%CI) for TV (1.2-11.8, p-trend <0.001), 8.2 for G2 (1.7-14.7, p-trend=0.008), and 15 months for P2 (8.2-22.1, p-trend <0.001). The highest versus lowest quartile of ΣDiNP was also associated with later pubertal onset, by 6.9 months for TV (1.5-12.4, p-trend=0.02), 7.8 for G2 (1.2-14.5, p-trend=0.03), and 8.9 months for P2 (1.7-16.1, p-trend=0.006). The highest versus lowest quartile of ΣDEHP was associated only with later P2, by 9.5 months (2.0-16.9, p-trend=0.008). Conclusion: On average, boys with higher prepubertal anti-androgenic MBzP, ΣDiNP, and ΣDEHP concentrations had later pubertal onset, ranging from six months to over a year. These phthalates may affect androgen signaling, in turn, impacting pubertal timing. Funding: NIEHS ES014370 & ES000002.
