Co-exposure to fluoride and arsenic induces endoplasmic reticulum stress in C2C12 myoblasts and MC3T3 preosteoblasts

Area of Science:

• Environmental toxicology
• Cellular biology
• Skeletal health

Background:

• Fluoride and arsenic are global environmental toxicants impacting skeletal development.
• Cellular mechanisms of combined fluoride and arsenic exposure on muscle and bone cells are poorly understood.

Purpose of the Study:

• To investigate the impact of sodium fluoride (NaF) and arsenic trioxide (As₂O₃) co-exposure on C2C12 myoblasts and MC3T3 preosteoblasts.
• To elucidate the cellular mechanisms, including oxidative and endoplasmic reticulum stress, involved in co-exposure toxicity.

Main Methods:

• Co-exposure of C2C12 myoblasts and MC3T3 preosteoblasts to NaF and As₂O₃.
• Assessed cell proliferation, lineage-specific transcription factor expression (MYOD, RUNX2), reactive oxygen species (ROS) production, and unfolded protein response (UPR) pathway activation.

Main Results:

• Co-exposure significantly reduced cell proliferation and MYOD/RUNX2 expression.
• Combined treatments elevated ROS production, with co-exposure causing the highest oxidative stress.
• Fluoride and arsenic co-exposure induced endoplasmic reticulum (ER) stress via UPR activation in both cell types.
• C2C12 myoblasts showed predominantly unresolved ER stress (PERK-Atf4-Chop activation), while MC3T3 cells exhibited adaptive responses (both PERK and IRE1α pathways activated).

Conclusions:

• Fluoride and arsenic co-exposure disrupts cellular homeostasis by inducing ER stress in both myoblasts and preosteoblasts.
• C2C12 myoblasts are more susceptible to co-exposure toxicity than MC3T3 preosteoblasts due to differential UPR pathway activation.