Developmental neurotoxicity of thyroid hormone system-disrupting chemicals: a systems-level exploration using...

There is increasing concern that thyroid hormone system-disrupting chemicals (THSDCs) may affect brain development during gestation and lactation. THSDCs comprise a wide range of natural and synthetic xenobiotics that activate diverse biological pathways. However, how disruption of specific molecular targets alters maternal thyroid hormone homeostasis and brain development in the offspring warrants further investigation. To address this question, this study investigates the effects of two THSDCs administered to pregnant rats from gestational day 6 through postnatal day 21: 5-propyl-2-thiouracil (PTU, 2.4 mg/kg/day), inhibitor of thyroid hormone synthesis, and pregnenolone-16α-carbonitrile (PCN, 300 mg/kg/day), inducer of hepatic enzymes involved in thyroid hormone metabolism. Circulating and brain thyroid hormone levels, enzymatic activities, and histopathology were assessed in dams and offspring. To further elucidate underlying mechanisms, multi-omics analyses combining proteomics, metabolomics, and spatial transcriptomics were performed on target organs including the thyroid gland, liver, and brain. Exposure to PTU resulted in severe thyroid hormone depletion in both serum and brain, accompanied by structural brain abnormalities, whereas PCN primarily induced hepatic enzyme activity with minimal effect on circulating thyroid hormone levels. Despite these distinct modes of action, multi-omics integration revealed convergent perturbations across molecular layers in the brain, particularly affecting energy metabolism and cytoskeletal organization with more pronounced effects observed following PTU exposure. Overall, multi-omics profiling enabled robust and highly sensitive identification of molecular signatures reflective of PCN exposure, without significant evidence of associated adverse toxicological effects. This approach highlights the value of multi-omics for mechanistic characterization and predictive assessment of THSDC-induced neurodevelopmental toxicity.