Protective Effect of Melatonin Against Bisphenol A Toxicity
Abstract
1. Introduction
1.1. Overview of BPA Toxicity
1.2. Overview of Melatonin and Its Potential Protective Effects
1.3. Purpose
2. BPA Toxicity
2.1. Sources of BPA Exposure
2.2. Mechanisms of BPA Toxicity
2.3. Effects of BPA Exposure on Health
3. Melatonin and Its Protective Effects
3.1. What Is Melatonin?
3.2. Antioxidant Properties of Melatonin
3.3. Anti-Inflammatory Properties of Melatonin
3.4. Other Mechanisms Underlying Protective Effects of Melatonin
4. Evidence of Protective Effects of Melatonin Against BPA Toxicity
4.1. In Vitro Studies
4.2. Animal and Preclinical Studies
5. Potential Applications of Melatonin for BPA-Induced Toxicity
5.1. Melatonin Dosage and Timing in Animal Models
5.2. Safety Considerations in Human
6. Comprehensive Research Framework
6.1. Summary of Findings
6.2. Implications for Public Health and Policy
6.3. Future Research Directions
6.3.1. Modulation of Specific Reproductive Signaling Pathways
6.3.2. Inhibition of ER Stress Pathways
6.3.3. Regulation of Autophagy via Transcription Factor EB (TFEB) and p38 MAPK Pathway
6.3.4. Inhibition of Ferroptosis Through KEAP1/NRF2/PTGS2 Axis and Ferritinophagy
6.3.5. Regulation of Mitochondrial Dynamics and Quality Control via SIRT1/PGC-1α Pathway
6.3.6. New Methods in Future Research
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Cancer Type | Specificity | Proposed Mechanism | BPA Concentration | Reference |
---|---|---|---|---|
Breast Cancer | General * | Endocrine disruption; promoting adipogenesis, lipogenesis, and adipokine secretion; creating a pro-inflammatory, nutrient-rich environment | Not specified | [36] |
ERα-positive cells | Synergizes with genistein to induce estrogenic responses, potentially epigenetically reprogramming breast cells | 50 nM | [37] | |
General | Induces differentiation of adipose cells into cancer-associated adipocyte-like cells, promoting epithelial–mesenchymal transition (EMT) via the CXCL12/AKT pathway | 10 nM | [38] | |
Prostate Cancer | General | Promotes biochemical recurrence and death by disrupting mitochondrial energy homeostasis, potentially via ESR1-PFKFB4 axis | In vitro and in vivo: 10 nM | [39] |
Ovarian Cancer | General | Promotes migration and invasion by activating the Wnt/β-catenin/SPP1 axis, leading to osteopontin secretion and transformation of fibroblasts into cancer-associated fibroblasts | In vitro: 10, 100 nM | [40] |
General | Alters epithelial diversity; induces apoptosis and necrosis; disrupts antioxidant, apoptotic, and inflammatory gene expression | Low dose 1 mg/kg body weight (BW), high dose 5 mg/kg BW | [41] | |
General | Induces oxidative stress, increasing production of ovarian cancer stem cells | Low dose 1 mg/kg BW, high dose 5 mg/kg BW | [42] | |
Endometrial Cancer | General | Low-dose BPA alters estrous cycle and uterine pathology in rats, with a gene signature predictive of survival in human patients with endometrial cancer | 25 and 250 μg/kg BW/day | [43] |
Colorectal Cancer | General | Enhances de novo ceramide synthesis, exacerbating tumor progression and EMT | In vitro: 0.01, 0.1, 1 µM; in vivo: low dose 0.62–1.14 μg/g, high dose 6.65–20.56 μg/g | [44] |
Obese rats | May worsen progression through the PI3K–AKT pathway and increase IL-1β levels | 25 mg/kg | [45] | |
General | Upregulates GOLPH3, promoting proliferation and migration | 1 µM | [46] | |
Colon epithelial cells | Increases cellular invasiveness and anchorage-independent cell growth, potentially through phosphorylation of various protein kinases | Low dose 0.0043 nM | [47] | |
Thyroid Cancer | Papillary thyroid carcinoma | Enhances proliferation and tumorigenesis through ROS generation and activation of NOX4 signaling pathways | 0.1 and 0.5 µM | [48] |
Liver Cancer | Hepatocellular carcinoma (in mice) | Alters gene expression in the liver, predicting hepatocellular carcinoma | 50 mg/kg | [49] |
Liver cells | Induces chemosensitivity and is associated with increased PPARγ expression in digestive system cancers | ~33.70 µg/mL | [50] |
Specificity of Protective Effect | Proposed Mechanism | Melatonin Concentration | Reference | |
---|---|---|---|---|
Ocular Diseases | Protects against ferroptosis in RPE cells in age-related macular degeneration | PI3K/AKT/MDM2/p53 pathway: increases phosphorylated PI3K, AKT, and MDM2, inhibiting p53 and restoring SLC7A11 expression | In vitro: 10–200 μM; in vivo: 10–40 mg/kg | [73] |
General protective and therapeutic potential for ocular diseases | Antioxidant, anti-inflammatory, immunomodulatory, neuroprotective, regulation of intraocular pressure, and VEGF secretion | Varies depending on disease and study | [74] | |
IOP-lowering and neuroprotection in glaucoma | Stimulation of melatonin receptors in the ciliary body; antioxidant and neuroprotective effects | Topical formulations: 0.1–17.2 mM | [75] | |
Antioxidant and neuroprotective effects in diabetic retinopathy | Reduction in oxidative stress and inflammation | Varies depending on study | [74] | |
Antioxidant protection and regulates ocular tissue functions | Direct scavenging of ROS, stimulation of antioxidant enzymes, interaction with melatonin receptors | 0.07–86 mM | [75] | |
Neurodegenerative Diseases | Protective activity in Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis | Antioxidant, modulates mitochondrial function and inflammation, synergistic effects with other neuroprotective agents | Optimal dosage has not yet been established in clinical settings | [76] |
Protection Against Electromagnetic Waves | Protects various organs (brain, skin, eyes, testis, kidney) against cell phone-induced electromagnetic waves | Strengthens cellular antioxidant system, mitigates oxidative stress and cell death | Animal studies: 2–100 mg/kg | [77] |
Wound Healing | Increases general wound healing (cuts, burns, ulcers) | Antioxidant, anti-inflammatory, and immunomodulatory actions, regulates vascular reactivity and angiogenesis | Physiological (pM) to pharmacological (μM) levels | [78] |
Skin Aging | Protection against age-related skin deterioration | Combats oxidative stress, shields from UV damage, curbs melanin production, and influences collagen synthesis and mitochondrial activity | Ex vivo: 100–200 µM | [79] |
Differential antiaging effects on epidermis and dermis | Downregulates mTORC1 activity and MMP-1, increases VEGF-A and fibrillin-1 expressions | Ex vivo: 100–200 µM | [80] | |
Cardiotoxicity | Protects against 5-fluorouracil-induced cardiotoxicity | Reduces oxidative damage, mitigates inflammation, attenuates the increase in cardiac biomarker levels | Rats: 2.5, 5, and 10 mg/kg/day | [81] |
Organ Fibrosis | Inhibition of fibrosis in liver, lung, heart, kidney, and skin | Antioxidant, anti-inflammatory effects, remodels extracellular matrix, suppresses EMT, regulates apoptosis | Oral administration: up to 500 mg/day | [7] |
Other Protective Effects | Mitigation of lead-induced oxidative stress in tobacco BY-2 suspension cells | Protects against lipid profile modification and membrane integrity | Not specified | [82] |
Increase in sleep quality in adults with various diseases | Not specified | Varies depending on study | [83] |
Specificity | Proposed Mechanism | Melatonin Concentration | BPA Concentration | Functions | References |
---|---|---|---|---|---|
Renal protection | Diminishing oxidative stress, maintaining redox equilibrium within mitochondria, sustaining mitochondrial function and architecture | In vivo: 10 mg/kg; in vitro preincubation: 0.1, 0.5, 1, 10, 100 µM; in vitro after BPA exposure: 0.5 µM | In vivo: 50, 100, 150 mg/kg; in vitro: 1–1000 µM; in vitro with melatonin: 125 µM | Damaging effects of BPA on the kidney and the protection by melatonin: emerging evidence from in vivo and in vitro studies | [94] |
Protection of testicular mitochondria | Antioxidant properties, direct free radical scavenging activity, lowering mitochondrial lipid peroxidation, restoring mitochondrial enzyme activity, and ameliorating decreased enzymatic and nonenzymatic antioxidants | In vivo: 1–10 mg/kg BW | In vivo: 10 mg/kg BW; environmentally relevant BPA doses: 25 μg/kg | Melatonin ameliorates BPA-induced biochemical toxicity in testicular mitochondria of mice | [95,121] |
Protection against cytotoxicity and genotoxicity in HGF, MKN45, and MSC cell lines | Antioxidant and free radical scavenging properties, reducing ROS and MDA levels, increasing GSH content, and preventing DNA damage | In vitro: 12, 23, 46, and 93 µg/mL | In vitro: 0.5, 5, 50, and 100 µg/mL; control for melatonin protection: 50 µg/mL | The primary route of human exposure to BPA is oral intake, which is associated with genotoxicity, oxidative stress, endocrine disruption, mutagenicity, and carcinogenicity in in vitro and in vivo models | [9] |
Protection against reproductive toxicity | Increases in sperm concentration, sperm viability, and testosterone serum levels, potentially through antioxidant properties and interaction with hormone receptors, antiapoptotic effects, and hormonal modulation | Varies across studies: 10–20 mg/kg BW | Varies across included studies: 25–250 μg/kg BW | Melatonin and vitamins as protectors against the reproductive toxicity of bisphenols | [84,93] |
Neuro-protection in rats | Reduction in oxidative stress (diminished MDA levels), modulation of ERK/NF-kB signaling pathway, attenuation of histopathological alterations in the hippocampus, improvement in behavioral changes | In vivo, oral administration: 20 mg/kg BW (MEL I), 40 mg/kg BW (MEL II) | In vivo, intraperitoneal administration: 1 mg/kg BW | Neurotoxicity of BPA and impact of melatonin administration on oxidative stress, ERK/NF-kB signaling pathway, and behavior in rats | [70,71] |
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Joo, S.S.; Yoo, Y.-M. Protective Effect of Melatonin Against Bisphenol A Toxicity. Int. J. Mol. Sci. 2025, 26, 7526. https://doi.org/10.3390/ijms26157526
Joo SS, Yoo Y-M. Protective Effect of Melatonin Against Bisphenol A Toxicity. International Journal of Molecular Sciences. 2025; 26(15):7526. https://doi.org/10.3390/ijms26157526
Chicago/Turabian StyleJoo, Seong Soo, and Yeong-Min Yoo. 2025. "Protective Effect of Melatonin Against Bisphenol A Toxicity" International Journal of Molecular Sciences 26, no. 15: 7526. https://doi.org/10.3390/ijms26157526
APA StyleJoo, S. S., & Yoo, Y.-M. (2025). Protective Effect of Melatonin Against Bisphenol A Toxicity. International Journal of Molecular Sciences, 26(15), 7526. https://doi.org/10.3390/ijms26157526