Association of exposure to synthetic phenols and metal(loid)s with early puberty in Spanish girls: a multicentric case-control study

Abstract

The incidence of precocious puberty (PP) and its variants in girls has increased over recent decades. Early-life exposure to endocrine disrupting chemicals (EDCs) may contribute to this trend. The purpose of this study is to investigate the association of exposure to several phenolic EDCs and metal(loid)s, both individually and as a mixture, with the risk of early puberty in Spanish girls. This multicentric case-control study recruited 182 girls aged 4-8 years diagnosed with PP (n = 101) or manifesting any sign of early puberty (premature thelarche: n = 74, other: n = 7) and 128 controls in six Spanish hospitals. Bisphenol, paraben, benzophenone (BzP), and metal(loid) concentrations were quantified in spot urine samples. Adjusted logistic regression and quantile g-computation models were used to assess associations of individual chemicals and their mixture, respectively, with risk of early puberty. Increased bisphenol A (BPA) exposure was associated with higher risk of overall early puberty [OR (95% CI) = 1.44 (1.19 - 1.73) per two-fold increase in urinary concentrations], PP [1.69 (1.26 - 2.27)], and premature thelarche [1.29 (1.05 - 1.58)]. Higher total BzPs (3rd tertile) and zinc (Zn) concentrations were also associated with higher risk of early puberty and PP. The mixture showed a significant effect on the risk of overall early puberty [OR (95% CI) = 1.20 (1.04 -1.38)], primarily driven by BPA. CONCLUSION: These findings suggest that exposure to BPA and BzPs may increase the risk of early puberty in girls. Longitudinal studies are warranted to confirm these findings. WHAT IS KNOWN: - Exposure to endocrine disrupting chemicals (EDCs), such as bisphenol A (BPA), may accelerate or delay puberty onset, but evidence remains limited and inconsistent. - Toxic metals with estrogenic properties such as cadmium have been poorly studied in relation to puberty timing. WHAT IS NEW: - Higher BPA, benzophenones, and Zn levels were associated with greater odds of early puberty, including PP and premature thelarche, in Spanish girls. - Mixture analysis indicated a significant combined effect on early puberty risk, mainly driven by BPA.