Flame Retardant TDCPP Binds Membrane Thyroid Hormone Receptor, Impairing Neurodevelopment

Tris (1,3-dichloropropyl) phosphate (TDCPP) is a high-production-volume organophosphate ester flame retardant, with maximum concentrations of several tens of micrograms per liter (μg/L) in ambient water. Despite that, its neurodevelopmental toxicity mechanisms remain poorly understood.

In a study published in the KeAi journal Environmental Chemistry and Ecotoxicology, a group of researchers from China reveal that TDCPP in zebrafish, at environmentally relevant doses, binds specifically to the membrane thyroid hormone receptor, integrin α_vβ₃. This binding rewires MAPK and calcium signaling pathways, causing motor neuron developmental defects and locomotor behavioral impairment, thereby laying the groundwork for the development of a novel adverse outcome pathway.”

“We documented that TDCPP stimulates neurodevelopmental toxicity by binding to the membrane thyroid hormone receptor, integrin α_vβ₃,” says corresponding author Prof. Jian Li from Beijing Normal University. “Given that integrin α_vβ₃ may serve as a specific target for organophosphate esters, this pilot finding necessitates a paradigm shift: the role of this membrane receptor should not be overlooked in evaluating the neurotoxicity of TDCPP, and even other organophosphate esters, in contrast to focusing on the traditional nuclear receptors.”

The team established a quantitative pathway mapping from TDCPP’s specific binding to integrin α_vβ₃, triggering activation of MAPK and calcium signaling cascades, which subsequently cause motor neuron development defects and ultimately lead to locomotor dysfunction.

“These quantitative relationships provide a predictive framework for extrapolating apical adverse outcomes based on preceding molecular responses, facilitating chemical hazard screening, testing prioritization, and comprehensive risk assessment,” adds Li. “For example, through rigorous quantitative analysis, the benchmark dose lower confidence limit values for TDCPP were determined to range from 3.83 to 82.56 μg/L.”

Notably, the lower threshold of this range aligns closely with environmental concentrations detected in surface waters and wastewater effluents, suggesting a potential risk elevation for aquatic organisms and warranting heightened environmental concern.

 “By establishing quantitative response-response relationships, this work serves as a foundation for developing a novel quantitative adverse outcome pathway framework,” says Li.

Contact:

Jian Li, Engineering Research Center of Groundwater Pollution Control and Remediation, Ministry of Education, College of Water Sciences, Beijing Normal University, Beijing 100875, China, lijian@bnu.edu.cn

Bingli Lei, Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China, leibingli@126.com

Funder:

This study was supported by the National Key Research and Development Program of China (2024YFC3908603) and the National Natural Science Foundation of China (42177255).

Conflict of interest:

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

See the article:

Li, J., et al., Adverse outcome pathway-oriented exploration of neurodevelopmental toxicity of tris(1,3-dichloropropyl) phosphate linked to membrane thyroid hormone receptor activation, Environmental Chemistry and Ecotoxicology, Volume 7, 2025, Pages 1261-1270, https://doi.org/10.1016/j.enceco.2025.06.006