Multiomic Landscape of Primary Hypothyroidism Induced by Subchronic Exposure to Low-Dose Novel PFOS Substitute OBS in Human and Murine Models

Sodium <i>p</i>-perfluorous nonenoxybenzenesulfonate (OBS) as a novel surrogate for perfluorooctanesulfonate (PFOS) has been extensively utilized in industrial manufacturing and daily life. However, studies on OBS-induced environmental health risks of obstructive biosynthesis (OBS) are currently limited, particularly the risk for thyroid diseases. Following the construction of <i>in vivo</i> (mouse) and <i>in vitro</i> (normal human primary thyrocytes) models of subchronic low-dose OBS exposure, we explored the thyroid-disrupting effects of OBS through multiomics approaches and experimental validations. Our results showed that subchronic exposure to low doses of OBS led to primary hypothyroidism in mice, presenting with reduced number and functional abnormalities of thyrocytes. Further <i>in vitro assays</i> confirmed that low-dose OBS-induced disulfidptosis, a newly discovered form of programmed cell death, in human primary thyrocytes. Meanwhile, exposure to low-dose OBS remarkably suppressed thyroid hormone synthesis pathways in mouse and human thyrocytes. The charted multiomic landscape of OBS-induced primary hypothyroidism in mammals revealed the thyroid toxicity and endocrine-disrupting properties of OBS, suggesting that it is not a safe alternative to PFOS.