Endocrine Disruption Rewards: Bisphenol-A-Induced Reproductive Toxicity and the Precision Ameliorative Potential of Flavonoids in Preclinical Studies. A Systematic Review and Meta-Analysis

Michael Ben Okon^1*ILEMOBAYO VICTOR FASOGBON¹Dominic Terkimbi Swase¹Reuben Samson Dangana²Wusa Makena¹Vivian Onyinye Ojiakor¹Monday Ekom Etukudo¹Joan Chebet¹Angela Mumbua Musyoka¹Sandra Etumah Ifie¹Herbert Mbyemeire¹Solomon Mbina¹Okechukwu Paul-Chima Ugwu¹Augustine Oviosun¹Micheal Usman Ibe¹JOSIAH IFIE³Loganathan Rangasamy⁴Sinbad Olorunnisola Olubukola¹Philippe Mounmbegna¹Sana Noreen⁵Patrick Maduabuchi Aja¹

• ¹Kampala International University - Western Campus, Bushenyi, Uganda
• ²University of KwaZulu-Natal - Westville Campus, Durban, South Africa
• ³Valley University of Science and Technology, Bushenyi, Uganda
• ⁴Vellore Institute of Technology, Vellore, India
• ⁵The University of Lahore, Lahore, Pakistan

Bisphenol A (BPA), a pervasive endocrine-disrupting chemical, impairs male reproductive health via oxidative stress, hormonal dysregulation, and hypothalamic pituitary gonadal (HPG) axis disruption. Flavonoids, widely present in plant-derived foods and medicinal herbs, possess antioxidant and steroidogenic modulatory properties that may counteract BPA toxicity, yet preclinical findings remain inconsistent. This study aims to systematically evaluate and quantitatively synthesise preclinical evidence on the protective effects of flavonoids against BPA-induced male reproductive toxicity. Using PRISMA 2020 guidelines, Web of Science, Scopus, and PubMed were searched up to September 2024. Eligible studies involved BPA exposure in male rodents with flavonoid co-treatment and reported reproductive endpoints. Hormonal and oxidative stress biomarkers were pooled using a random effects model, expressed as standardised mean differences (SMDs), with heterogeneity assessed by I² statistics. Twenty studies were included. BPA significantly reduced testosterone (SMD = −4.91), oestradiol (SMD = −2.72), follicle-stimulating hormone (SMD = −7.71), and luteinising hormone (SMD = −5.54) while increasing malondialdehyde and reducing antioxidant enzymes (SOD, CAT, GPx, and GSH). Flavonoid co-treatment significantly improved hormonal profiles and oxidative balance, with the greatest recovery in FSH. High heterogeneity (I² > 84%) reflected variability in doses, treatment duration, compound purity, and species. Flavonoids exhibit marked ameliorative potential against BPA-induced reproductive toxicity in preclinical models, largely through hormonal regulation and oxidative stress mitigation. Standardised protocols and dose–response studies are essential to enhance reproducibility and translational relevance.