In vitro human brain barrier models for studying thyroid hormone transport

Area of Science:

• Neuroscience
• Developmental Biology
• Toxicology

Background:

• Thyroid hormone (TH) is essential for fetal brain development, and its disruption is linked to cognitive and motor deficits.
• Current animal models for assessing TH disruption lack human relevance and raise ethical concerns.
• New Approach Methodologies (NAMs), particularly in vitro models, are needed for accurate human-relevant risk assessment.

Purpose of the Study:

• To review the development and application of in vitro models for studying thyroid hormone transport across developing human brain barriers.
• To highlight the importance of considering the dynamic changes in the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) during development.
• To explore how these models can investigate chemical disruption of TH transport and its impact on brain development.

Main Methods:

• Review of current in vitro models, from simple mono-cultures to complex 3D and organ-on-chip systems, for modeling human brain barriers.
• Focus on human cell-based models that mimic the cellular composition and function of the BBB and BCSFB.
• Integration of models that account for developmental time points and barrier interplay.

Main Results:

• Developing in vitro models, including organ-on-chip systems, offer a more human-relevant approach to study TH transport.
• These models can incorporate the role of specific TH transmembrane transporters (THTMTs) like MCT8 and OATP1C1.
• The models facilitate the investigation of how chemical disruptors affect TH transport and subsequent brain development.

Conclusions:

• Accurate in vitro models of human brain barriers are crucial for understanding TH transport and disruption.
• These NAMs can replace or reduce reliance on animal testing for developmental neurotoxicity assessments.
• Further development and validation of these advanced in vitro models are essential for robust risk assessment of chemical exposures during critical developmental windows.