Superfood or Silent Threat? Milk Thistle Extracts and Their Impact on Neurodevelopmental Health

Milk thistle, specifically its extract known as silymarin, has attracted attention for its hepatoprotective and antioxidant properties, primarily attributed to its active flavonolignan compounds. However, this natural supplement presents potential risks, particularly during pregnancy, due to its selective and potent inhibition of monocarboxylate transporter 8, blocking cellular uptake of thyroid hormones. While being involved in various processes in the adult body, the disruption of thyroid hormone homeostasis during fetal development has been associated with various neurodevelopmental disorders, leading to intellectual disabilities, speech impairments, and motor coordination challenges. To comprehensively assess the hazards posed by such chemicals, risk assessors are moving toward a knowledge-driven approach transitioning away from traditional animal models and embracing alternative methodologies. Leveraging the concept of Adverse Outcome Pathways (AOPs) as a knowledge organization framework from scientific literature and data, we aim to delve into the mechanistic underpinnings of these toxicological processes. In this study, we exploit the AOP-Wiki, a central repository of AOPs, employing semantic web technologies to construct an intricate AOP network elucidating how perturbations in thyroid hormone homeostasis result in neurodevelopmental adversities. We further supplement this knowledge with insights from RNA-sequencing data on hypothyroidism in neuroprogenitor cells. Our findings shed light on the multifaceted impact of thyroid hormone disruption, extending beyond neurogenesis to encompass the various signaling and metabolic processes. These revelations underscore the intricate reprogramming of neuroprogenitor cells under hypothyroid conditions, affecting a myriad of neurodevelopmental processes. Nevertheless, the complexity of these mechanisms and the gaps in our comprehension of thyroid hormone's role necessitate the execution of targeted assays to validate these effects. This research endeavor represents a pivotal step in unraveling the complex interplay between thyroid hormones and neurodevelopment, shedding light on potential hazards associated with substance mixtures like silymarin and advancing our knowledge-driven approach to toxicity assessment. Poster presented at NUTRIM Symposium 2023, Maastricht (2023).