Does zearalenone bind estrogen receptors and disrupt male reproductive hormone signaling?

Zearalenone (ZEN) is a prominent mycoestrogen produced by Fusarium fungi. Because of its structural similarity to endogenous estrogens, it functions as a potent endocrine disruptor that alters male reproductive physiology.

Estrogen receptor binding

• Receptor affinity: ZEN acts as a competitive ligand against 17β-estradiol, directly binding human recombinant estrogen receptors. It displays moderate binding affinity in the nanomolar-to-submicromolar range, with IC50 values of approximately 240.4 nM for ERα and 165.7 nM for ERβ.
• Metabolic activation: Its hepatic metabolite, α-zearalenol, exhibits even higher potency, binding both ER subtypes with low-nanomolar affinity to strongly mimic endogenous estrogens.

Endocrine disruption and testicular toxicity

• HPG axis suppression: Direct estrogen receptor binding activates negative feedback loops on the hypothalamic-pituitary-gonadal (HPG) axis, centrally suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
• Steroidogenic inhibition: Peripherally, ZEN targets Leydig cells to directly inhibit testosterone biosynthesis. It downregulates critical steroidogenic enzymes, including steroidogenic acute regulatory protein (Star), Cyp11a1, Cyp17a, and Hsd17b3.
• Oxidative stress: ZEN exposure increases reactive oxygen species (ROS), compromises mitochondrial membrane potential, and induces germ-cell apoptosis and DNA fragmentation within testicular tissues, resulting in impaired sperm quality.

Bottom line

• Zearalenone binds human estrogen receptors to suppress central gonadotropin secretion and downregulate key Leydig cell steroidogenic enzymes. This dual mechanism reduces testosterone production, promotes testicular oxidative stress, and impairs overall male reproductive function.