Methionine‐Mediated H3K4me3 Reduction by Caffeine Intake Regulates Embryonic Viability and Oxidative Stress Resistance in Caenorhabditis elegans

ABSTRACT

Maternal nutrition influences fertility and offspring health, with effects often transmitted across generations. Although caffeine intake has been linked to both beneficial and adverse outcomes, the molecular mechanisms underlying its intergenerational effects remain poorly understood. This study investigated whether maternal caffeine intake affects embryonic viability and offspring physiology through methionine‐dependent alterations in H3K4me3 using Caenorhabditis elegans (C. elegans) . C. elegans mothers were fed caffeine and examined for changes in H3K4me3 levels, eggshell integrity, and stress physiology. Maternal caffeine intake reduced global H3K4me3 levels, and a reduction was also observed in adult offspring. Caffeine‐fed mothers showed increased eggshell permeability from 9.9% to 27.8% and embryonic lethality from 2.4% to 5.2%. These changes were accompanied by reduced expression of cbd‐1 and perm‐1 , which contribute to vitelline layer and permeability barrier formation. Methionine supplementation restored global H3K4me3 levels, reduced eggshell permeability and embryonic lethality, and partially recovered the expression of eggshell formation genes, cbd‐1 and perm‐1 . Surviving offspring from caffeine‐fed mothers showed no significant changes in the expression of the examined eggshell formation genes but exhibited enhanced oxidative stress resistance with DAF‐16 nuclear localization. Therefore, maternal caffeine intake was associated with methionine‐dependent H3K4me3 reduction and distinct developmental and physiological outcomes in mothers and surviving offspring.