Associations of perinatal phthalate/alternative exposure with precocious puberty in girls: Higher odds for incomplete subtype and potential mitigation by vitamin supplementation

Due to regulatory restrictions, traditional metabolites of phthalates (e.g., plasticizer di-(2-ethylhexyl) phthalate) are being replaced by alternatives such as di-(isononyl)-cyclohexane-1, 2-dicarboxylate and di(2-propylheptyl) phthalate. The metabolites of the alternatives are widely found in human urine, but their association with potential health outcomes remain largely unknown. Epidemiological evidence linking perinatal exposure to traditional phthalates and their emerging alternatives with precocious puberty (PP) in girls remains sparse, and potential differences in their effects on clinical subtypes are unknown. This study aimed to analyze the association of maternal exposure to phthalates and their alternatives during pregnancy with PP odds in female offspring, assess subtype-specificity for incomplete precocious puberty (IPP, gonadotropin-independent) and central precocious puberty (CPP, gonadotropin-dependent), and explore the role of steroid hormones in the association and effect modification by maternal vitamin supplementation. We included 87 cases of CPP, 115 cases of IPP, and 606 matched controls in this (nested case-control) study based on the Wuhan Healthy Baby Cohort. Twenty-five metabolites of phthalates/alternatives (mPAEs) and thirteen steroid hormones were measured in maternal urine samples collected during late pregnancy. We employed multivariable logistic regression, Bayesian kernel machine regression (BKMR), and quantile-based g-computation (qgcomp) to assess single and mixture effects. Mediation analyses were used to evaluate the roles of the steroid hormones in the association, and subgroup analyses were used to evaluate the modification effect of vitamin supplementation. Higher maternal mono-methyl phthalate (MMP) level in the highest quartile (Q4) was related with elevated PP odds (Q4 vs. the lowest quartile, Q1: OR = 3.15; 95% CI: 1.57, 6.25). The associations were significantly specific to IPP, involving MMP (Q4 vs. Q1: OR = 3.07; 95% CI: 1.45, 6.48), metabolites of diisononyl phthalate [mono-(4-methyl-7-hydroxy-octyl) phthalate and mono-(4-methyl-7-oxo-octyl) phthalate], and a phthalate alternative metabolite mono-(6-oxo-2-propylheptyl). No significant associations were observed for CPP. Mixture analysis identified MMP as the primary contributor (19%). progesterone (P4) mediated 34% of the MMP-IPP association (indirect effect: 0.02; 95% CI: 0.01, 0.04). Crucially, maternal vitamin supplementation appeared to attenuate the adverse associations between the mPAEs and PP. Perinatal exposure to specific phthalates is associated with elevated odds of PP in girls, with stronger effects in the IPP subtype. The association may be partially mediated by altered maternal P4 levels. Our findings also suggested, for the first time, that maternal vitamin supplementation might mitigate these odds. This is also the first time to report the association between the metabolites of phthalate alternatives and PP odds.