Abstract
The epidemiological studies regarding perfluorooctanoic acid (PFOA) suggests that its exposure causes reproductive health issues, the underlying mechanisms of which are still in its infancy. Here, we report that PFOA deteriorates female reproduction at multiple development stages. Oocyte meiosis and preimplantation development are severely impaired by PFOA with oxidative stress being a contributor. Supplementing with antioxidant melatonin partially rescues oocyte meiotic maturation and non-apoptotic demise. The attenuation in ovarian follicle development however can be improved by metformin but not melatonin. Importantly, metformin blunts PFOA-induced fetal growth retardation (FGR) and such protective effect could be recapitulated by transplantation of fecal material and pharmacological activation of AMPK. Mechanistically, PFOA causes gut microbiota dysbiosis, which might thereby rewire host metabolism of L-phenylalanine, histamine and L-palmitoylcarnitine that triggers hyperphenylalaninaemia, inflammation and ferroptosis to initiate FGR. Deregulated serine metabolism by the gut microbe constitutes an alternative mechanism underlying PFOA-induced FGR in that modulation of serine in dam's diet phenocopied the FGR. Our study expands the understanding of risk factors that impair human reproductive health, and proposes restoration of gut microbiota diversity and intervention of metabolism as therapeutics mitigating health risks predisposed by environmental perturbation.