Serine Ameliorates Cadmium-Induced Testicular Injury by Regulating the PGAM1/PHGDH Signaling Pathway

Cadmium (Cd) is a widespread environmental contaminant that impairs male reproductive function; however, the metabolic mechanisms underlying Cd-induced testicular toxicity remain incompletely understood. This study investigated whether serine supplementation could alleviate Cd-induced testicular injury and explored its association with phosphoglycerate mutase 1 (PGAM1)- and phosphoglycerate dehydrogenase (PHGDH)-related serine metabolism. Forty male C57BL/6 mice were randomly assigned to four groups and received ultrapure water, serine (50 g/L), Cd (50 mg/L), or Cd plus serine in drinking water for 18 weeks. Testicular morphology, hormone levels, ion homeostasis, oxidative stress, inflammation, glycolytic metabolism, fibrosis, apoptosis, and the expression of PGAM1/PHGDH-related proteins were evaluated. Cd exposure induced marked testicular injury, characterized by reduced testicular weight and index, disrupted reproductive hormone levels, histopathological damage, ion imbalance, oxidative stress, inflammatory responses, and decreased expression of blood-testis barrier-associated proteins. Cd also suppressed glycolysis and serine biosynthesis, as evidenced by reduced activities of glycolytic enzymes, decreased lactate and pyruvate production, lower serine levels, inhibited PHGDH, PSAT1, and PSPH expression, and altered PGAM1 expression. These changes were accompanied by increased fibrosis and germ cell apoptosis. Serine supplementation substantially ameliorated these abnormalities, restoring metabolic homeostasis, improving antioxidant capacity, reducing inflammation, and attenuating fibrosis and apoptosis. In conclusion, serine exerts a strong protective effect against Cd-induced male reproductive toxicity by counteracting metabolic dyshomeostasis, highlighting its potential therapeutic value as a beneficial additive against heavy metal-associated reproductive damage.