Maternal Excessive Lard Versus Palm Oil Intake in Mice Drives Sex-Specific Reproductive Dysfunction in Offspring

Objectives: This study clarified sex-specific short- and long-term impacts of maternal excessive palm oil (plant-derived saturated) and lard (animal-derived saturated fat) intake on offspring reproductive health and underlying mechanisms. Methods: Female mice were randomized to control, palm oil, or lard diets during gestation and lactation. Offspring received a control diet post-weaning until adulthood, followed by an optional 16-week HFD rechallenge. Gonadal weight and organ index, sperm quality, ovarian follicle number, serum sex hormones, metabolic phenotypes (serum lipid profiles, glucose and insulin tolerance), oxidative stress, apoptosis, proliferation, and transcriptomic profiles were detected at weaning, early and late adulthood. Results: In males, excessive maternal lard intake significantly induces sperm malformation and reduces seminiferous tubule diameter and spermatogenic epithelium thickness upon HFD rechallenge during adulthood, with no changes in oxidative stress, proliferation, and apoptosis. Transcriptomics identified Slc24a5 upregulation as a potential correlate through metal ion transmembrane transporter activity and cellular calcium ion homeostasis. Under normal adult diets, reduced sperm motility resulting from maternal excess lard may be mediated by apoptosis, whereas that induced by maternal high palm oil likely arises from suppressed proliferation and thinner spermatogenic epithelium. GO analysis revealed palm oil-specific Ugt1a5 upregulation associated with altered steroid hormone metabolism. In females, maternal palm oil intake reduced primordial follicles and increased atresia, with sequencing predicted to involve Nedd4 downregulation; lard intake elevated ovarian oxidative stress and atresia only upon HFD rechallenge, with Lamc3 upregulation predicted as a putative regulatory factor. Conclusions: Maternal excessive intake of saturated fat exerts offspring reproductive damage in a sex-specific and source-dependent manner with distinct mechanisms. This work provides novel insights into fat source-dependent and sex-specific effects of nutritional interventions during pregnancy and lactation.