Association between phthalate exposure and early puberty: An updated meta-analysis exploring sex and exposure time variations

Puberty is a critical developmental stage, and its early onset, termed precocious puberty, has garnered attention because of its potential health and psychosocial implications. Environmental exposure to endocrine-disrupting chemicals (EDCs), including phthalates, has been associated with alterations in pubertal timing; however, the evidence remains inconsistent. This meta-analysis investigated the association between exposure to specific phthalate metabolites and early puberty; the study focused on the effects of sex and exposure timing (prenatal vs. postnatal). We conducted a systematic search to identify studies examining phthalate exposure and early puberty, covering research published between 2014 and 2024. This search yielded 29 relevant studies, of which 13 met our inclusion criteria and were selected for analysis. A previously published meta-analysis had synthesized data from these same 13 studies, aligning with our research objectives. Due to reporting heterogeneity across the additional studies, our analysis focused on these 13 studies. Random-effects models were applied to estimate pooled relative risks (RRs), with data stratified by sex and exposure timing. Meta-regression and subgroup analyses were performed to evaluate the effects of demographic and temporal factors. The results indicated limited associations between most phthalates and early puberty risk. Postnatal exposure to mono-n-butyl phthalate was modestly associated with an increased risk of early puberty in boys (RR: 1.03; 95% confidence interval [CI]: 1.01-1.06), whereas exposure to mono-(3-carboxypropyl) phthalate was associated with a slight reduction in the risk of early puberty in girls (RR: 0.955; 95% CI: 0.917-0.995). However, these associations were not significant after adjustment for urine specific gravity, suggesting the presence of measurement variability or residual confounding. Subgroup and meta-regression analyses revealed no significant modifying effects of sex or exposure timing. Publication bias assessments indicated no substantial asymmetry. Despite these observed patterns, definitive conclusions cannot be drawn because of data limitations, small sample sizes, and methodological inconsistencies. Future research should prioritize standardized exposure and outcome reporting, larger cohorts, and investigation into the cumulative effects of phthalates with other EDCs. This study demonstrates the complexity of the effects of phthalates on pubertal timing and the need for more rigorous investigations to guide public health interventions.