Methoxyacetic acid and ethoxyacetic acid inhibit mitochondrial function in vitro

Area of Science:

• Toxicology
• Biochemistry
• Cell Biology

Background:

• Ethylene glycol monomethyl ether (EGME) and ethylene glycol monoethyl ether (EGEE) are recognized reproductive toxicants in animal models.
• Their toxicity is attributed to their metabolites: methoxyacetic acid (MAA) and ethoxyacetic acid (EAA).
• Target tissues exhibit rapid cell division and high energy demands, suggesting mitochondrial involvement.

Purpose of the Study:

• To investigate the effects of EGME, EGEE, and their metabolites (MAA, EAA) on mitochondrial function.
• To determine if MAA and EAA directly impact mitochondrial respiration and enzyme activity.
• To correlate mitochondrial dysfunction with the known reproductive toxicity of EGME and EGEE.

Main Methods:

• Isolated hepatic mitochondria were used to assess mitochondrial respiration (state 3) and respiratory control ratio (RCR) with various substrates.
• Cytochrome c oxidase activity was measured in the presence of MAA and EAA.
• Mitochondrial function in testicular tissue was also examined for MAA effects.

Main Results:

• MAA and EAA significantly inhibited state 3 respiration and RCR in hepatic mitochondria at concentrations as low as 3.85 mM.
• Both metabolites also inhibited cytochrome c oxidase activity at similar concentrations.
• MAA demonstrated comparable inhibitory effects on testicular mitochondria.
• EGME and EGEE did not affect mitochondrial function at high concentrations.

Conclusions:

• The findings support the hypothesis that MAA and EAA mediate the reproductive toxicity of EGME and EGEE.
• MAA and EAA exert their toxic effects, at least in part, by impairing mitochondrial function.
• Mitochondrial inhibition is a key mechanism underlying the reproductive toxicity of these glycol ethers.