Citrus flavanones show preclinical promise against BPA male reproductive harm, review finds

A new narrative review concludes that the citrus compounds naringenin and naringin can counter several damaging effects of bisphenol A on the male reproductive system, but only in laboratory and animal models, and that the evidence falls far short of supporting any supplement recommendation for men concerned about fertility. The review, published on 13 October 2026 in Basic and Clinical Andrology, was led by Okon Michael Ben and colleagues and synthesised studies published mainly between January 2019 and September 2026, while retaining older work of direct mechanistic relevance. Its central message is deliberately cautious: the strongest evidence for harm from bisphenol A comes from convergent cellular and animal data backed by heterogeneous human observational studies, while the strongest evidence for the two flavanones remains preclinical, resting on a single Sertoli-cell study of naringenin and a single adult-rat study of naringin that directly used bisphenol A.

Bisphenol A is a synthetic compound used in polycarbonate plastics, epoxy resins, thermal papers and food-contact materials, and its ubiquity makes reproductive relevance a live public-health question. Regulatory interpretations differ sharply: the European Food Safety Authority lowered the tolerable daily intake in 2023, whereas the United States Food and Drug Administration states that approved food-contact uses are safe at current exposure levels. The review’s authors argue that this divergence makes it essential to separate evidence of biological hazard from questions of exposure realism and human causal inference. In male reproductive biology, bisphenol A is not limited to one site of action. It can interact with estrogen receptors and androgen-related signalling, alter steroidogenic pathways, and affect Sertoli-cell function, Leydig-cell activity, germ-cell survival, blood-testis barrier integrity, sperm maturation and the molecular composition of sperm itself.

The mechanistic picture assembled in the review is broad. Experimental studies link bisphenol A to disrupted endocrine signalling and impaired steroidogenesis, with reduced testosterone concentrations and altered expression of genes and proteins involved in steroid hormone synthesis. Oxidative stress emerges as one of the most consistent pathways: sperm are especially vulnerable because their plasma membranes are rich in polyunsaturated fatty acids and mature sperm carry little cytoplasmic antioxidant reserve, so excess reactive oxygen species can damage lipids, proteins, mitochondrial membranes and DNA, reducing motility, distorting morphology and impairing fertilising capacity. Mitochondrial dysfunction adds another layer, with impaired membrane potential, reduced ATP production, increased mitochondrial reactive oxygen species and altered mitophagy all reported after exposure. Bisphenol A can also shift the balance of germ-cell proliferation and controlled apoptosis toward cell loss, reducing spermatogenic output and degrading seminiferous tubule architecture.

Human evidence, by contrast, remains inconsistent and cannot establish causation. A meta-analysis of nine studies covering 2,399 men found a small inverse association with sperm motility that was not robust after adjustment for publication bias and sensitivity analysis, while a later synthesis of 18 studies reported small inverse pooled associations with sperm concentration (β = -0.03, 95% CI -0.06 to -0.01) and total count (β = -0.05, 95% CI -0.08 to -0.02) but no robust association with below-reference semen quality. Endpoint-specific results add further nuance. In 195 Spanish men, higher urinary bisphenol A and bisphenol F were associated with lower sperm vitality; in 158 healthy Spanish university students, bisphenol A was not significantly associated with sperm DNA fragmentation in a chemical-mixture analysis; and repeated urinary measurements in 474 Chinese infertility-clinic patients linked bisphenol A with greater comet-assay tail length and tail distributed moment. These cross-sectional findings differ in population, exposure assessment and outcome, and the review treats them as important for public-health relevance but not as proof of causality.

Developmental experiments add an offspring dimension that the review handles with unusual terminological care. In one mouse experiment, maternal gavage with 50 mg/kg/day bisphenol A from embryonic day 0.5 to 18.5 was followed by lower testis weight, testosterone, sperm count, motility and acrosomal integrity in F1 males, together with impaired sperm-oocyte binding and impaired early embryo development, with statistical significance reported at p < 0.05. Because those F1 animals were directly exposed in utero, the findings are intergenerational and do not by themselves demonstrate transgenerational inheritance, a distinction the authors reserve for designs extending to the F2 or F3 generations. The high experimental dose also limits extrapolation to typical human exposure, and the review stresses that individual prenatal and perinatal studies are not uniform enough to claim that every exposure produces persistent dysfunction. Replication at environmentally relevant internal doses and follow-up beyond F1 are identified as priorities.

Against this backdrop, the direct bisphenol-A-specific evidence for the flavanones is strikingly narrow. Naringenin is a citrus flavanone, and naringin is its glycoside, converted partly to naringenin by intestinal microflora. In the key cellular study, Khorsandi and colleagues exposed mouse TM4 Sertoli cells to 0.8 µM bisphenol A for 24 hours and tested naringenin at 10, 20 and 50 µg/mL. Bisphenol A reduced viability (p = 0.004), mitochondrial membrane potential (p < 0.001) and antioxidant biomarkers (p = 0.003), while increasing reactive oxygen species, malondialdehyde, PINK1 and Parkin (p < 0.001). Naringenin at 20 and 50 µg/mL improved viability and membrane potential (p = 0.034), and concentration-dependent treatment reduced PINK1/Parkin expression (p = 0.024). The review frames this as direct BPA-specific mechanistic evidence in one immortalised cell line, explicitly not evidence of restored fertility.

The other direct study is equally circumscribed. Alboghobeish and colleagues assigned 42 adult male Wistar rats to six groups of seven and administered bisphenol A at 50 mg/kg with or without oral naringin at 40, 80 or 160 mg/kg for 30 days. Naringin improved several bisphenol-A-altered biochemical, hormonal, sperm-count and histological measures, reported as statistically significant in the article. Yet the review notes that this single study, the high bisphenol-A dose and the absence of replication in humans limit the strength of any efficacy claim. Evidence from other reproductive stress models is labelled supportive only. In 42 adult male Wistar rats, oral naringin at 80 mg/kg three times weekly for eight weeks improved testosterone, sperm count, motility, viability, redox markers and histology after di-n-butyl phthalate exposure at 250 or 500 mg/kg (p < 0.05), and in 30 rats naringin at 50 mg/kg for 28 days improved selected hormonal, testicular-injury, redox and histological measures in a high-fat-diet and streptozotocin diabetes model. Neither study tested bisphenol A, and the review insists that shared pathways across toxicants provide biological context but cannot establish protection against bisphenol A or justify pooling effect sizes.

The pharmacokinetic picture is equally incomplete. In a randomised single-dose crossover trial of 18 healthy adults, 150 to 900 mg of naringenin produced dose-related systemic exposure without relevant short-term adverse events, with a reported half-life of approximately 2.7 to 3.0 hours. That trial informs exposure and short-term safety only; it did not measure reproductive outcomes or testicular exposure. The review poses the translational question bluntly: whether administered flavanone doses produce sustained, unconjugated concentrations in testicular tissue that modify injury without adverse effects. It also cautions that molecular endpoints may be exposure-sensitive but are not yet validated surrogates for infertility or embryo outcomes, citing a cross-sectional cohort of 102 Portuguese men in whom seminal-plasma bisphenol A was not significantly correlated with conventional semen parameters even though small-RNA and proteomic subsets showed differential molecular profiles.

Methodologically, the review is transparent about its own limits. Because the search was narrative, no PRISMA flow diagram, formal risk-of-bias tool or pooled quantitative analysis was used, and the evidence tables are representative rather than exhaustive. Differences in species, bisphenol-A dose, route, timing, duration, flavanone dose and semen-analysis methods prevent direct comparison across studies, and differences in model, dose, route and bioavailability prevent quantitative comparison of the flavanone literature. The authors propose a research agenda that includes environmentally relevant doses alongside higher mechanistic doses, internal exposure measurements, clearer attention to gestational, lactational, pubertal and adult exposure windows, F2 and F3 designs when inheritance beyond directly exposed generations is claimed, integrated endpoint panels combining sperm variables with hormones, histology, oxidative stress, mitochondrial function, apoptosis and sperm DNA fragmentation, and pharmacokinetic bridging that measures parent compounds, conjugated metabolites and testicular concentrations after repeated oral dosing.

The bottom line is a firm boundary between mechanism and medicine. The review states that the available studies identify redox, mitochondrial, endocrine and histological endpoints for further testing but do not support prescribing naringenin or naringin for fertility, and that human studies should avoid supplement claims until carefully designed clinical or observational research has established safety, feasibility and relevance. Improvement in motility or viability in a model does not establish restoration of spermatogenesis, and normalisation relative to a high-dose toxicant group does not establish clinical benefit. What the findings do justify is better-designed mechanistic research with exposure-relevant doses, pharmacokinetics, integrated sperm and testicular endpoints, functional fertility outcomes such as fertilisation rate, sperm-egg binding, acrosome reaction, embryo development and offspring health, and appropriate multigenerational designs. Until that evidence arrives, the review concludes, reducing bisphenol exposure and evaluating replacement bisphenols remain the primary public-health approach, with flavanone research positioned as a complement to chemical regulation rather than a substitute for it.

Subject of Research: Preclinical evidence for naringenin and naringin protection against bisphenol A–induced male reproductive toxicity

Article Title: Protective effects of naringenin and naringin against bisphenol A–induced male reproductive toxicity: mechanistic and preclinical evidence

Article References: Ben, O. M., Okechukwu Paul-Chima, U., Iyore, I. C., Olubukola, O. S., Philippe, M., & Maduabuchi, A. P. (2026). Protective effects of naringenin and naringin against bisphenol A–induced male reproductive toxicity: mechanistic and preclinical evidence. Basic and Clinical Andrology, 36(1), Article 28. https://doi.org/10.1186/s12610-026-00330-4

Image Credits: AI Generated

DOI: 10.1186/s12610-026-00330-4

Keywords: bisphenol A, naringenin, naringin, male fertility, sperm quality, oxidative stress, mitochondrial dysfunction, Sertoli cells, endocrine disruption, testicular toxicity, flavanones, narrative review