Nuclear Receptor Networks as the Central Hub of Endocrine-Disrupting Chemical Neurotoxicity: A System Toxicology Perspective

Endocrine-disrupting chemicals (EDCs) are ubiquitous environmental contaminants linked to rising neurodevelopmental disorders, yet the neurotoxicity of real-world low-dose mixtures remains poorly understood. This review establishes a conceptual framework positioning the nuclear receptor (NR) superfamily as the central integrative hub, where structurally diverse EDC signals converge. Transcending traditional single-chemical paradigms, we detail how mixtures co-opt the NR network through molecular crosstalk, heterodimer competition, and epigenetic reprogramming. Such disruptions trigger pathogenic cascades, including dysregulated neuroinflammation, impaired synaptic plasticity, and bioenergetic collapse, that compromise brain development. We critically evaluate state-of-the-art experimental and computational models, from brain organoids to microphysiological systems, advocating for an integrated systems toxicology approach. Leveraging time-series multiomics and dynamic network modeling is essential to identify mechanistic thresholds and assess potential transgenerational risks. This NR-centered framework provides a robust foundation for evolving the discipline from descriptive toxicology to predictive, next-generation risk assessment, ultimately safeguarding brain health in an increasingly complex chemical environment.