Early-life phthalate mixture exposure and reproductive hormone levels during minipuberty

Background: Phthalates (PAEs) are ubiquitous endocrine-disrupting chemicals (EDCs) with well-documented prenatal effects, while their impact during early postnatal life remains less understood. Minipuberty, a transient activation of the hypothalamic-pituitary-gonadal (HPG) axis in early infancy, represents a critical window of endocrine programming. This study aimed to investigate the association between early-life exposure to PAEs and urinary reproductive hormone levels during minipuberty in healthy term-born infants. Methods: This longitudinal study included infants from the Modena birth cohort with repeated urine sampling at birth (T0), 3 (T3), and 6 months (T6). Urinary concentrations of PAE metabolites (MMP, MEP, MnBP, MBzP, SDEHPm) and urine reproductive hormones (uLH, uFSH, uT and uE) were measured. Associations were assessed using sex-stratified Spearman correlations, single-pollutant linear regression models, and mixture approaches, including Weighted Quantile Sum (WQS) regression and quantile g-computation (qgcomp). Results: PAE metabolites were evaluated in 162 infants and detected in nearly all samples, confirming widespread exposure. Consistent positive associations emerged between PAE exposure and urinary hormone levels. In males, increasing levels of metabolites were significantly associated particularly with increased uFSH and uT, at all timepoints. In females, associations were more evident at T3 and T6, mainly involving uFSH and uE. Mixture analyses confirmed these findings and identified MnBP, MBzP, and SDEHPm as the main contributors. Results were consistent across methods, highlighting a mixture association beside an isolated compound-specific findings. Conclusion: Early-life exposure to PAE mixtures is associated with sex-specific alterations in reproductive hormone levels during minipuberty. These findings highlight minipuberty as a sensitive window for endocrine disruption and underscore the importance of considering chemical mixtures in environmental health research. However, further studies are needed to determine whether these early hormonal perturbations may have implications for long-term reproductive development and health.