Exposure to Synthetic Phenols and Metal(loid)s and Neuroendocrine Effect Biomarkers in Spanish Girls with and Without Early Puberty

Exposure to endocrine-disrupting chemicals (EDCs) is widespread and may influence pubertal timing in girls through changes in neuroendocrine signaling. This study investigated the association of exposure to phenolic EDCs and metal(loid)s, individually and as a mixture, with neuroendocrine effect biomarker levels in girls with and without early puberty. A multicenter case–control study recruited 182 girls manifesting signs of early puberty and 128 controls (4–8 years) in six Spanish hospitals. Synthetic phenols, metal(loid)s, and brain-derived neurotrophic factor (BDNF) concentrations were quantified in spot urine samples (n = 309), while serum total BDNF, pro-BDNF, mBDNF, and kisspeptin levels were measured in a sub-sample of 47 cases. Associations were evaluated using linear regression, WQS and g-computation models. Higher urinary concentrations of total parabens were associated with increased urinary BDNF and serum total BDNF and mBDNF levels. Higher cadmium levels were associated with lower urinary BDNF and higher benzophenones, lead, and copper levels with lower serum pro-BDNF. The overall chemical mixture was associated with lower urinary BDNF, with bisphenol A, arsenic, and cadmium identified as the main contributors. Higher urinary BDNF was associated with lower odds of early puberty. Exposure to certain phenolic EDCs and metal(loid)s is associated with alterations in BDNF levels, supporting the need for longitudinal studies to confirm these associations and clarify underlying mechanisms.