Friend and Foe?: Metals as Facilitators and Disruptors of Steroid Nuclear Receptor Signaling

Steroid hormone signaling, transduced by nuclear receptors (NRs), is essential for mammalian physiology. Like other transcription factors, NRs are structurally and functionally influenced by essential and non-essential metal ions. Here, we provide a scoping review of the role metal ions play in NR signal transduction, focusing on class I steroid hormone receptors (androgen, estrogen, glucocorticoid, mineralocorticoid, and progesterone). Biochemical assessments, prior to and concomitant with the advent of NR cloning, suggest metal-mediated modification of NR ligand binding domains, cytosolic chaperone complexes, and zinc finger DNA binding domains as crucial mechanisms of metal-by-NR interactions. Subsequent molecular studies indicate that metals differentially affect NRs, largely driven by a metals' valence state (divalent, trivalent, etc). Some toxic metals can directly activate NRs. Despite six decades of work, crucial gaps in our knowledge of metal-by-NR effects remain, including in vitro to in vivo extrapolations, incorporation of mixture effects, and further delineation of direct and indirect receptor activation. This review concatenates how trace elements affect steroid hormone NR activity and identifies future areas of research that could mitigate metal-induced endocrine disruption.