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. 2025 Nov 24:7:1687862.
doi: 10.3389/ftox.2025.1687862. eCollection 2025.

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 Fasongbon  1 , Dominic Swase  1 , Reuben Samson Dangana  2 , Wusa Makena  3 , Vivian Onyinye Ojiakor  3 , Ekom Monday Etukudo  3 , Joan Chebet  1 , Angela Mumbua Musyoka  1 , Sandra Etumah Ifie  1 , Herbert Mbyemeire  1 , Solomon Adomi Mbina  1 , Okechukwu Paul-Chima Ugwu  4 , Augustine Oviosun  3 , Ibe Micheal Usman  3 , Josiah Eseoghene Ifie  5 , Loganathan Rangasamy  6 , Olubukola Sinbad Olorunnisola  1 , Philippe Mounmbegna  1 , Sana Noreen  7 , Patrick Maduabuchi Aja  1
Affiliations

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 et al. Front Toxicol. .

Abstract

Introduction: 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 synthesize preclinical evidence on the protective effects of flavonoids against BPA-induced male reproductive toxicity.

Methods: 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 standardized mean differences (SMDs), with heterogeneity assessed by I2 statistics. Twenty studies were included.

Results: BPA significantly reduced testosterone (SMD = -4.91), estradiol (SMD = -2.72), follicle-stimulating hormone (FSH) (SMD = -7.71), and luteinizing hormone (SMD = -5.54), while increasing malondialdehyde and reducing antioxidant enzymes (SOD, CAT, GPx, and GSH).

Discussion: 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. Standardized protocols and dose-response studies are essential to enhance reproducibility and translational relevance.

Keywords: bisphenol A; endocrine disruption; flavonoids; meta-analysis; oxidative stress; preclinical studies; reproductive toxicity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Risk of bias for the various domains.
FIGURE 2
FIGURE 2
Risk of bias assessment for the individual articles.
FIGURE 3
FIGURE 3
PRISMA study selection flow chart.
FIGURE 4
FIGURE 4
Geographic distribution of study contributions by country (%).
FIGURE 5
FIGURE 5
Percentage of phytochemical analysis methods used in studies.
FIGURE 6
FIGURE 6
Interplay of the flavonoid on testosterone levels following BPA exposure.
FIGURE 7
FIGURE 7
Interplay of the flavonoid on estradiol levels following BPA exposure.
FIGURE 8
FIGURE 8
Interplay of the flavonoid on follicle-stimulating hormone levels following BPA exposure.
FIGURE 9
FIGURE 9
Interplay of the flavonoid on luteinizing hormone levels following BPA exposure.
FIGURE 10
FIGURE 10
Interplay of the flavonoid on SOD levels following BPA exposure.
FIGURE 11
FIGURE 11
Interplay of the flavonoid on CAT levels following BPA exposure.
FIGURE 12
FIGURE 12
Interplay of the flavonoid on reduced glutathione levels following BPA exposure.
FIGURE 13
FIGURE 13
Interplay of the flavonoid on GPx levels following BPA exposure.
FIGURE 14
FIGURE 14
Interplay of the flavonoid on MDA levels following BPA exposure.
See this image and copyright information in PMC

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