Sex-Dependent PlacentalNeuroendocrine Disruptionby Maternal Arsenic Exposure: From Neurotransmitter Dysregulationto Neurobehavioral Outcomes

Abstract Epidemiological evidence suggests that developmental arsenic (As) exposure increases behavioral abnormalities in offspring. However, how placental neuroendocrine function and sex-specific responses contribute to these effects remains poorly understood. Here, we demonstrate that maternal As exposure induces trophoblastic damage, vascular disruption, and placental labyrinth thinning, leading to placental dysplasia, fetal growth restriction, and sex-specific behavioral outcomes in offspring. Integrated transcriptomic and neurobehavioral analyses revealed sex-dependent alterations primarily involving neurodevelopmental pathways and transporter dysfunction. Concurrently, neurotransmitter metabolomic profiling identified profound disturbances in tryptophan, tyrosine, and amino acid metabolism in the placenta and fetal brain. Bayesian benchmark dose (BMD) modeling revealed that points of departure (PoDs) followed the rank order, such that metabolomic (mPoDs) < neurobehavioral (nPoDs) < apical (aPoDs). Notably, alterations in the tryptophan pathway were the most sensitive early perturbations observed, with BMDL10 values for 5-hydroxy-l-tryptophan of 3.73 μg/L in females and 4.17 μg/L in males, respectively. Overall, this exploratory framework provides evidence for placental neuroendocrine toxicity of As and highlights its potential relevance for refined environmental risk assessment.