The antifoulant 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) is an emerging pollutant in the marine environment, which may disrupt the thyroid endocrine system. However, DCOIT toxicity in relation to thyroid endocrine disruption and the underlying mechanisms remains largely unclear. In this study, in vivo, in silico, in vitro, and ex vivo assays were performed to clarify DCOIT’s thyroid toxicity. First, marine medaka (Oryzias melastigma) were exposed to environmentally realistic concentrations of DCOIT for an entire life cycle. The results demonstrated that DCOIT exposure potently stimulated the hypothalamic−pituitary−thyroid axis, characterized by hyperthyroidism symptom induction and prevalent key gene and protein upregulation in the brain. Moreover, the in silico and in vitro results evidenced that DCOIT could bind to thyroid hormone receptor β (TRβ) and interact synergistically with triiodothyronine, thus promoting GH3 cell proliferation. The CUT&Tag experiment found that DCOIT interfered with the affinity fingerprint of TRβ to target genes implicated in thyroid hormone signaling cascade regulation. Furthermore, ex vivo, Chem-seq revealed that DCOIT directly bound to the genomic sequences of thyrotropin-releasing hormone receptor b and thyroid-stimulating hormone receptor in marine medaka brain tissues. Hence, the current multifaceted evidence confirmed that DCOIT has a strong potency for thyroid endocrine system disruption and provided comprehensive insights into its toxicity mechanisms. In addition, parental life-cycle exposure to 1, 3, and 10 μg/L DCOIT led to transgenerational impairment of cardiogenesis in offspring medaka. A crossbreeding strategy discriminated a concentration-dependent mechanism of transgenerational cardiotoxicity. At 1 μg/L, the DCOIT-exposed female parent transferred a significantly higher amount of triiodothyronine (T3) hormone to offspring, corresponding to an accelerated heart rate. However, DCOIT at higher exposure concentrations modified the methylome imprinting in larval offspring, which was associated with cardiac dysfunction. Sub-chronic exposure to DCOIT at 1, 3, 10, and 33 μg/L validated that cardiac defects were caused by upregulation of cardiac gene transcriptions, decreasing heart size, and accelerating heartbeat. Hyperthyroidism in medaka larvae was identified as the cause of developmental cardiotoxicity of DCOIT sub-chronic exposure. Overall, the findings provide novel insights into the thyroid endocrine disruption and parental implications in transgenerational toxicity of DCOIT. The high risks of DCOIT—even at environmentally realistic concentrations—raise concerns about its applicability as an antifoulant in a marine environment.

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