Folic acid deficiency damages male reproduction via endoplasmic reticulum stress-associated PERK pathway induced by Caveolin-1 in mice.

ABSTRACT

Folic acid is critical to maintaining normal male reproductive function. Endoplasmic reticulum (ER) stress plays a crucial role in folic acid deficiency. Studies have shown that Caveolin-1 (Cav-1) is involved in ER stress, but the specific mechanism in male reproduction is still unclear. This study aimed to investigate the effects of folic acid deficiency on spermatogenesis and elucidate the underlying mechanisms. C57BL/6 mice fed with folic acid deficiency induced diet(0.3 mg/kg) were used. A significant decrease in the sperm concentration in the folic acid deficiency group was observed. Meanwhile, folic acid deficiency decreased Cav-1 expression in the testis tissue and increased endoplasmic reticulum stress-related PERK, eIF2α, ATF4, CHOP gene expression. Our results suggest that folic acid deficiency can affect male reproduction through the Cav-1-PERK-eIFα-ATF4-CHOP pathway.Abbreviations ATF4 activating transcription factor 4; Ca2+ calcium ion; Cav-1 Caveolin-1; CCK-8 cell counting kit-8; CHOP CCAAT-enhancer-binding protein homologous protein; DNA Deoxyribonucleic acid; DSB double strand breakage; eIF2α eukaryotic Initiation Factor 2 alpha; ER endoplasmic reticulum; FD folic acid deficiency; FITC fluorescein isothiocyanate; HE hematoxylin and eosin; H3K4me3 histone H3 lysine 4 trimethylation; PERK protein kinase RNA-like endoplasmic reticulum kinase; PI propidium iodide; RT-qPCR quantitative reverse transcription PCR; TUNEL TdT mediated dUTP Nick End Labeling.