Evolution of Nuclear Receptors as Environmental Chemical Sensors: Structural Innovation and Signaling Expansion

Abstract Nuclear receptors (NRs) are a superfamily of ligand-regulated transcription factors that translate chemical signals to gene regulatory responses. Although traditionally viewed through the lens of endocrinology, mounting evolutionary and comparative evidence demonstrate that nuclear receptors originated as environmental chemical sensors long before the emergence of complex hormonal systems. From their appearance in early branching metazoans, more than 700 million years ago, the nuclear receptor superfamily has undergone extensive structural and functional diversification driven by ligand availability, dimerization strategies, and local- and genome-scale duplication and loss. An important step in this expansion was the emergence of the retinoid X receptor (RXR) as a common heterodimerization partner, allowing several receptor pathways to be linked to metabolism, development, and xenobiotic responses. Here, we review the evolutionary history of nuclear receptors with a focus on structural innovations in the ligand binding domain, the emergence of RXR-centered networks, and the role of nuclear receptors as master regulators of the chemical defensome. We further synthesize insights from environmental toxicology and comparative genomics to show how nuclear receptor evolution can help us understand species-specific sensitivity to environmental pollutants and modern chemical exposures.