Beyond Nephrotoxicity: Maternal-Fetal Transfer of Melamine and Potential Disruption of Placental Steroid Hormones

The widespread use of melamine (MEL) and its derivatives has resulted in pervasive human exposure, yet their transplacental transfer and developmental consequences remain insufficiently characterized. In a mother-infant cohort, we quantified four MEL derivatives in matched maternal urine (median: 31.9 ng/mL), maternal blood (1.10 ng/mL), amniotic fluid (15.0 ng/mL), and cord blood (2.01 ng/mL), demonstrating substantial fetal exposure. Transplacental transfer efficiencies of MEL, ammelide, and cyanuric acid (CYA) were 1.46, 1.36, and 1.64, respectively, and were inversely correlated with their log K_ow values. Maternal MEL concentration was negatively associated with birth weight, particularly in female infants (10^β = 90.5%, 95% CI: 83.0%, 98.9%), estriol mediating approximately 30.7% of this effect. BeWo assays demonstrated that MEL derivatives cross the placental barrier via combined passive diffusion and transporter-modulated processes, involving folate-related transporters together with multiple xenobiotic transport systems. In trophoblast cells, coexposure to MEL and CYA (1:9) at environmentally relevant concentrations suppressed estradiol and estriol secretion in a nonmonotonic, dose-dependent manner, accompanied by down-regulation of key steroidogenic enzymes and compensatory up-regulation of estrogen receptors. Overall, this study provides integrated evidence that MEL analogues may cross the placenta via nutrient-mimicking transport pathways and disrupt placental steroidogenesis, potentially impairing fetal growth.