Erucic acid impairs male fertility by suppressing retinoic acid synthesis in sertoli cells

Abstract

Although dietary factors are increasingly implicated as crucial determinants of male fertility, specific dietary risk factors and their metabolic mechanisms remain poorly understood. In this study, patients with non-obstructive azoospermia (NOA) or severe oligospermia (EO) demonstrated significantly elevated erucic acid (EA) levels, with a nearly 3-fold increase in serum (P < 0.0001) and a 27 % increase in semen (P = 0.0147) compared to controls, suggesting a potential dose-dependent negative impact of EA exposure on spermatogenesis. Mice fed a high-EA diet exhibited a significant 52.5 % reduction in sperm concentration compared with the control group, indicating impaired reproductive function (P < 0.0001). Mechanistic experiments in testicular organoid (TO) models have demonstrated that high-dose erucic acid (EA) directly interferes with meiotic progression. Transcriptomic analysis revealed significant disruptions in retinol metabolism pathways, which are essential for regulating spermatogenesis. The key gene involved in retinoic acid (RA) biosynthesis, retinol dehydrogenase (Rdh10), showed an approximate 38.5 % decrease in expression (P = 0.0467). Liquid chromatography-mass spectrometry (LC-MS) further confirmed that elevated EA levels significantly suppressed RA synthesis in Sertoli cells (P = 0.0078). The underlying molecular mechanism involves the binding of EA to the GPR120 receptor, which subsequently downregulates the expression of Rdh10. Co-culture experiments with Sertoli cells and spermatogonial stem cells complemented by TO assays demonstrated that RA supplementation may be a promising therapeutic strategy to reverse EA-induced meiotic and spermatogenic impairment. These findings provide novel insights into how prolonged dietary EA exposure adversely affects male reproductive health by disrupting retinol metabolism and RA signalling pathways and offer evidence for defining dietary EA safety thresholds and informing policies to safeguard male fertility.

Keywords: Dietary lipids; Erucic acid; GPR120; Male infertility; Retinoic acid synthesis; Sertoli cells; Testicular organoids.