Docosahexaenoic Acid and the Gut-Ovarian Axis: A Potential Protective Role Against Environmental Endocrine-Disrupting Chemical-Induced Female Reproductive Toxicity

Abstract: The global burden of female infertility is substantial and rising, with environmental endocrine-disrupting chemicals (EEDs) now recognized as important modifiable contributors. Bisphenol A (BPA), phthalates, and their analogues have been shown to impair folliculogenesis, steroidogenesis, oocyte quality, and endometrial receptivity. These toxicants also reshape the gut microbiota, damage intestinal barrier integrity, and promote metabolic endotoxemia, thereby amplifying systemic inflammation and endocrine perturbations. Docosahexaenoic acid (DHA), a long-chain n-3 polyunsaturated fatty acid, exerts anti-inflammatory, antioxidant, and pro-resolving activities, and is increasingly recognized as a modulator of the gut microbial ecosystem. This review proposes that DHA may antagonize EED-induced female reproductive toxicity through a gut-ovarian axis, by (i) restoring microbial diversity and beneficial taxa, (ii) strengthening tight-junction integrity and reducing lipopolysaccharide translocation, (iii) blunting Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB)-mediated inflammation, and (iv) directly protecting granulosa cells and oocytes against oxidative stress. The strongest available evidence comes from DHA-enriched phosphatidylserine, which attenuates BPA-induced intestinal injury via restoration of Akkermansia , Butyricicoccus , and Lachnospiraceae and inhibition of TLR4/NF-κB signaling. Translational data from polycystic ovary syndrome models and in vitro oocyte maturation studies further support an ovary-protective role of n-3 fatty acids. However, ovarian protection mediated by the gut microbiota remains unproven: the strongest available data derive from rodent models with intestinal rather than ovarian endpoints, and human evidence is largely limited to metabolic and inflammatory outcomes that cannot be equated with preserved follicles or improved fertility. Responses may also vary with genetic background. Future studies should integrate multi-omics of the gut microbiota, metabolome, bile acids, and ovarian transcriptome, and evaluate DHA formulation, dose, and timing in at-risk populations. Keywords: docosahexaenoic acid, endocrine-disrupting chemicals, gut microbiota, gut-ovarian axis, ovarian toxicity, environmental pollutants