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Updated: May 9, 2025

Author Spotlight: Studying the Impact of Maternal Dietary Deficiencies on Long-Term Offspring Health Outcomes
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Author Spotlight: Studying the Impact of Maternal Dietary Deficiencies on Long-Term Offspring Health Outcomes

Published on: June 28, 2024

305

Methotrexate-induced disruption of the serum-glucocorticoid inducible protein kinase 3 signaling pathway and its

Onju Ham1, Soontag Jung1, Ye-Ji Kim2

  • 1Center for Regulatory Toxicology Research, Laboratory of Developmental and Reproductive Toxicology, Korea Institute of Toxicology, Deajeon 34114, Republic of Korea.

Journal of Hazardous Materials
|May 6, 2025
PubMed

Insights

Methotrexate (MTX) exposure harms developing brain organoids by increasing oxidative stress and apoptosis, impacting neuronal development. Folic acid treatment and understanding the SGK3 pathway may mitigate these neurotoxic effects.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Environmental Toxicology

Background:

  • Methotrexate (MTX) is a vital chemotherapeutic and immunosuppressive drug with environmental persistence.
  • MTX contamination in drinking water poses potential human health risks, particularly concerning developmental neurotoxicity.
  • The precise mechanisms by which MTX affects brain development are not fully understood.

Purpose of the Study:

  • To investigate the developmental neurotoxicity of Methotrexate (MTX) using brain cortical organoids (COs).
  • To elucidate the underlying molecular mechanisms of MTX-induced neurotoxicity in developing brain models.
  • To assess the potential protective effects of folic acid against MTX neurotoxicity.

Main Methods:

  • Exposure of brain cortical organoids (COs) to Methotrexate (MTX).
  • Assessment of oxidative stress, endoplasmic reticulum stress, and apoptosis.
  • RNA sequencing (RNA-seq) to identify molecular pathways affected by MTX.
  • RNA interference (siRNA) to validate the role of SGK3.
  • Analysis of calcium homeostasis.

Main Results:

  • MTX exposure increased reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and apoptosis in COs.
  • MTX affected immature neurons, GABAergic neurons, and astrocytes.
  • Folic acid treatment reversed MTX-induced cellular damage.
  • MTX significantly downregulated serum/glucocorticoid-regulated kinase 3 (SGK3).
  • SGK3 inhibition mimicked MTX effects, confirming its role in brain development.
  • MTX disrupted calcium homeostasis in COs.

Conclusions:

  • MTX induces developmental neurotoxicity in brain organoids by increasing ROS and ER stress, leading to apoptosis via SGK3 pathway inhibition.
  • Disrupted calcium homeostasis and altered neuronal cell expression contribute to abnormal brain development following MTX exposure.
  • These findings highlight the neurotoxic potential of MTX and the need for careful clinical consideration, especially during pregnancy.
Keywords:
Cortical organoidsDevelopmental neurotoxicityFolic acidMethotrexateSGK3 signaling pathway

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