β-caryophyllene mitigates metabolic dysfunction in the testes of gerbils perinatally exposed to BPA.

Bisphenol A (BPA) is a persistent environmental pollutant harmful to male reproductive health. Although linked to testicular disorders, the underlying mechanisms and potential therapeutic agents to mitigate their adverse effects need to be fully explored. We investigated the impacts of perinatal BPA exposure and the therapeutic potential of β-caryophyllene (BCP) in the testes of adult Mongolian gerbils (Meriones unguiculatus). Pregnant females were exposed to a historically relevant and realistic dose of BPA (50 μg/kg/day) during gestation and lactation. The F1 male offspring were maintained until adulthood and received a 30-day treatment with BCP (50 mg/kg/day). We assessed the biometric, hormonal, sperm motility, oxidative markers, and metabolic testicular parameters. BPA-exposed gerbils showed decreased progressive sperm motility, as well as increased non-progressive sperm movement. ¹H-NMR metabolomics revealed testicular metabolic reprogramming, including deficits in central energy metabolism (e.g., acetate), nucleoside biosynthesis (adenosine, IMP), vitamin metabolism (pyridoxine, taurine), and phospholipid integrity (ethanolamine, O-phosphoethanolamine). Pathway analysis revealed disturbances in pyruvate metabolism/gluconeogenesis, purine metabolism, and glycerophospholipid metabolism, confirming altered testicular homeostasis. Notably, the BCP consumption rescues sperm motility and mitigates BPA-induced metabolic dysfunction by restoring testicular contents of acetate, adenosine, inosine, IMP, ethanolamine, and O-phosphoethanolamine. Perinatal exposure to BPA programs latent testicular dysfunction through the establishment of a toxic metabolic memory that manifests in adulthood. However, the 30-day BCP intervention mitigated BPA-induced testicular metabolic dysfunctions. This study provides novel descriptive insights into BPA-induced testicular toxicity and highlights BCP as a promising therapeutic agent to counteract the long-term reproductive consequences of early-life exposures.