Are thyroid hormone–mediated mechanisms an overlooked pathway in male reproductive toxicity?

Thyroid hormones (THs) regulate key developmental processes, including neurogenesis, growth, and metabolism. They are essential for brain and skeletal development, as well as for the differentiation of multiple organs, acting primarily through nuclear TH receptors that modulate gene transcription. THs also influence testis development, primarily by regulating the proliferation and differentiation of Sertoli and Leydig cells. During early postnatal life, THs promote the cessation of Sertoli cell proliferation and their maturation, ultimately determining testis size. Despite important functions of TH signaling in other organs, regulatory testing for TH-system-disrupting chemicals has predominantly focused on neurodevelopment. With TH signaling influencing reproductive development, effects on male reproductive endpoints mediated by TH disruption may currently be underrepresented in regulatory frameworks for identifying endocrine-disrupting chemicals. Few mechanistic adverse outcome pathways, biomarkers, or sensitive testing windows have been established for these potential toxicity pathways, a gap that could increase the risk of not detecting chemicals that impair male reproductive health and fertility via TH-mediated mechanisms. Addressing these deficiencies is important to fully assess the reproductive risks posed by TH-system-disrupting compounds.