Thyroid Endocrine\nDisruption and Mechanism of the\nMarine Antifouling Pollutant 4,5-Dichloro-2-n-octyl-4-isothiazolin-3-one

The antifoulant 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one\n(DCOIT)\nis an emerging pollutant in the marine environment, which may disrupt\nthe thyroid endocrine system. However, DCOIT toxicity in relation\nto thyroid endocrine disruption and the underlying mechanisms remains\nlargely unclear. In this study, <i>in vivo</i>, <i>in silico</i>, <i>in vitro</i>, and <i>ex vivo</i> assays were performed to clarify DCOIT’s thyroid toxicity.\nFirst, marine medaka (Oryzias melastigma) were exposed to environmentally realistic concentrations of DCOIT\nfor an entire life cycle. The results demonstrated that DCOIT exposure\npotently stimulated the hypothalamic–pituitary–thyroid\naxis, characterized by hyperthyroidism symptom induction and prevalent\nkey gene and protein upregulation in the brain. Moreover, the <i>in silico</i> and <i>in vitro</i> results evidenced\nthat DCOIT could bind to thyroid hormone receptor β (TRβ)\nand interact synergistically with triiodothyronine, thus promoting\nGH3 cell proliferation. The CUT&Tag experiment found that DCOIT\ninterfered with the affinity fingerprint of TRβ to target genes\nimplicated in thyroid hormone signaling cascade regulation. Furthermore, <i>ex vivo</i>, Chem-seq revealed that DCOIT directly bound to\nthe genomic sequences of thyrotropin-releasing hormone receptor b\nand thyroid-stimulating hormone receptor in marine medaka brain tissues.\nIn conclusion, the current multifaceted evidence confirmed that DCOIT\nhas a strong potency for thyroid endocrine system disruption and provided\ncomprehensive insights into its toxicity mechanisms.