Role of antioxidant vitamins in mitigating the health risks from environmental toxicant exposures: a narrative review.

Studies in animals highlight the potential protective role of AVs, particularly vitamins C and E, in mitigating adverse health effects from environmental exposures, as summarized in Fig. 1 . These benefits are thought to stem from their integration into complex antioxidant defense networks where different antioxidant molecules interact. For example, vitamin C can regenerate oxidized vitamin E, boosting total antioxidant capacity [ 171 ]. However, because these antioxidants act within interconnected networks, the effect of supplementing one vitamin can be influenced by the existing balance of other antioxidant molecules, the oxidative state of the environment, and the underlying biological context [ 172 ]. Consequently, supplementation outcomes may be nonlinear and, at high doses, can even be pro-oxidant. This complexity has prompted interest in the reactive species interactome, a multilevel redox regulatory system that enables organisms to efficiently sense and adapt to environmental stressors [ 173 ]. Given these intricacies and the risk of unintended effects, it remains challenging to develop evidence-based dosing recommendations for AVs in humans to counteract effects of environmental toxicant exposure. Efficacy, safety, and optimal dosing remain to be clarified prior to any recommendations for intervention, particularly given the potential risk for adverse effects with inappropriate supplementation. Systemic protective roles of antioxidant vitamins against environmental toxicants: insights from animal studies. The tissues affected are listed in rectangle boxes, vitamins showing protective effects are indicated in hexagonal boxes, and the protective effect of intervention is indicated by a blunt-end arrow. The timing and route of AV supplementation is a critical determinant of its effectiveness in modulating the adverse effects of environmental exposures. Most animal studies have examined coadministration, where the vitamin is given concurrently with the toxicant while fewer have explored pretreatment or posttreatment. Evidence indicates that the protective efficacy of supplementation can vary substantially depending on timing. For example, in heavy metal toxicity, coadministration of vitamin C was more protective than posttreatment [ 174 ]. In contrast, for ultraviolet B–induced skin damage, pretreatment was more effective than posttreatment, highlighting the importance of tailoring supplementation strategies both to the nature of the toxicant and the exposure context [ 175 ]. The route and mode of vitamin administration further contribute to variability. Animal studies differ in whether vitamins are delivered with food or water, administered by oral gavage, or injected subcutaneously or intraperitoneally. Additionally, supplementation may be provided as a dietary additive, a single bolus, or in repeated doses, with the duration ranging from acute to chronic exposure periods. These methodological differences including timing, administration route, dosing regimen, and exposure duration complicate direct comparisons between studies and the extrapolation of findings to clinical or public health recommendations. The route of vitamin administration significantly influences its pharmacokinetics. For example, oral vitamin C results in tightly regulated plasma concentrations, whereas intravenous administration can achieve higher plasma levels [ 176 , 177 ], explaining its pro-oxidant nature when administered subcutaneously [ 133 ]. The heterogeneity among studies in terms of exposure duration, dosage, combinations of antioxidants, life stage, and species of study animals all contribute to the challenges in deriving broadly applicable conclusions from these studies. To enhance the translatability of findings to humans, it is essential to standardize study designs and ensure detailed reporting of these critical variables. Evaluating the modifying effect of AVs in human cohorts is challenging due to methodological inconsistencies in vitamin intake and status assessment. Most observational cohort studies do not quantify serum level of vitamins and rely on self-reported dietary intake using food frequency questionnaires (FFQs) (see Supplementary Table S1 [ 90 ]), which can vary markedly in length, specificity, and validation status. Examples include the 77-item Dutch EPIC FFQ [ 154 ], 101-item [ 150 ], abbreviated 39-item FFQs [ 178 ], 33-item [ 179 ], and 24-hour recall methods [ 152 ] that have been used in cohort studies investigating the modifying role of vitamins on adverse effects from exposure. Some estimate oxidative balance scores from these intakes [ 151 ], while others used household food purchases as a nutrient intake proxy, which poorly reflects individual bioavailability [ 148 ]. While randomized trials in humans help balance baseline dietary intake across study arms, thereby reducing confounding, variability in participants’ baseline antioxidant exposure can still introduce imprecision in the estimated effects of vitamin supplements [ 180 ]. Moreover, clinical trials typically use fixed vitamin doses without considering individuals’ starting diet or serum levels, which might overlook the full spectrum of antioxidant intake and potentially affect the accuracy of study findings. Accurately assessing long-term vitamin intake and absorption presents a major methodological challenge, particularly when studies rely on participant-reported dietary data and varied supplement types, thus complicating interpretation. Direct measurement of AV concentrations in plasma provides a more objective assessment and can overcome some of the biases inherent in dietary questionnaires. This can be done using high-performance liquid chromatography, which is considered the gold standard for vitamins A, C, and E, although commercially available colorimetric and radio assays could also be used. An ideal approach to studying the moderating effect of AVs on health effects should include a combination of FFQs and measures of serum vitamin levels as done in a small clinical trial studying the effect of antioxidant supplementation on lung functions among asthmatic children exposed to high levels of air pollutants [ 149 ]. It is understandable that this approach may not always be feasible in large or retrospective cohorts due to budget and logistic constraints such as sample storage and stability. For example, vitamin C’s photosensitive nature and rapid degradation in plasma (half-life ∼30 minutes) can result in undetectable levels if biospecimens are not properly handled [ 181 , 182 ]. Analytical approaches also vary, with some studies stratifying subjects by arbitrary antioxidant thresholds or comparing high- and low-intake groups. However, median cutoff values can differ substantially by population and ethnicity, contributing to inconsistent results. All of these factors must be taken into consideration while interpreting epidemiological studies of AVs. Another limitation in the current literature is the inconsistency of dosing protocols across and within animal and human studies, making comparison challenging. Antioxidant effects are dose dependent with protective benefits seen only at specific, higher concentrations in animal models [ 95 , 183 ]. In humans, more than 400 IU of vitamin E is necessary to reduce systemic oxidative stress [ 184 ], yet the absorption and efficacy of supplemental vitamin E remain low without concurrent dietary fat [ 185 ]. The efficacy of dietary antioxidants also differs in efficacy or mechanisms based on their source, with plant-derived antioxidants providing higher antioxidant content than animal sources [ 55 , 186 ]. Nonvitamin dietary components with antioxidant properties, such as selenium, lycopene, flavonoids, tannins, and phenols, also contribute substantially to the overall dietary antioxidant capacity. In observational studies, these elements may act as confounders, since they are often consumed alongside specific vitamins, making it difficult to attribute outcomes to a single vitamin. At certain doses, AVs can exert pro-oxidant effects, potentially worsening outcomes if not carefully managed. It is therefore essential to confirm whether supplementation effectively elevates plasma vitamin levels or affects oxidative stress biomarkers [ 187 ]. Vitamin A remains understudied for environmental exposures, likely due to concerns about increased lung cancer risk from β-carotene (pro–vitamin A) supplements [ 188 , 189 ] and its potential pro-oxidant effects at high doses given its regulatory role in gene expression [ 190 , 191 ]. Similarly, high-dose vitamins E and C in pregnant women at risk for preeclampsia have been linked to increased low birthweight [ 192 ], and vitamin E supplementation during early pregnancy was associated with reduced birthweight [ 193 ], though this was not seen in healthy pregnancies [ 194 ]. Dietary differences between groups may influence these findings. These conflicting results underscore the need to consider dose, population, and context, especially in sensitive groups like pregnant women. Clinical trials should incorporate serum or plasma vitamin measurements both in intervention and control groups, recognizing that habitual dietary intake precludes a true placebo condition. Interestingly, a vast majority of the animal studies on AVs and environmental exposures have been conducted exclusively in males. Among those that included both sexes, very few specifically investigated sex-specific responses to AV intervention [ 84 , 103 ]. In human research, there are some studies focusing solely on women or including more female participants, but most continue to examine either male or female cohorts separately. One study of sex-specific responses demonstrated that combined supplementation with vitamins C and E protected against smoking-induced DNA damage in females, but not in males [ 137 ]. This sex difference is further supported by evidence indicating the presence of sex specificity in oxidative stress, with females possessing a more robust antioxidant defense system and exhibiting a more efficient response to oxidative stress and environmental chemicals [ 195-197 ]. These differences likely result from variations in sex hormones, metabolic pathways, and gene expression related to antioxidant enzymes. Given these observations and the considerable knowledge gap, it is imperative for future research to systematically address the effect of AVs in women, particularly during pregnancy and in the context of environmental chemical exposures, to inform tailored and effective interventions. Real-world human exposures typically involve temporal coexposures, which is the simultaneous or sequential exposure to multiple environmental chemicals over extended periods of time [ 198 ], making it challenging to extrapolate findings from animal studies using single agents to humans. Furthermore, there is substantial interindividual variability across the human population in terms of (i) the exposome (the sum of all exposures over a lifetime), (ii) response to environmental stressors [ 199 , 200 ], and (iii) metabolism of dietary and supplementary antioxidants [ 201 , 202 ]. This complexity highlights the need for personalized nutritional interventions, which account for variability in genetics, metabolism, and lifestyle. Addressing these challenges requires interdisciplinary, data-driven approaches, including large, multicenter cohort studies to characterize redox phenotypes, reactive species interactome, and nutrigenomics [ 203 , 204 ] to identify avenues for personalized intervention. The integration of these concepts with artificial intelligence and computational tools could accelerate the development of effective, personalized antioxidant interventions. Nonetheless, any consideration of AVs should adhere to established dietary guidelines, including recommended dietary allowances and tolerable upper intake levels for vitamins A, C, and E [ 205 ]. Current evidence does not support widespread use of high-dose antioxidant supplementation. For most individuals, achieving the daily recommended intakes of 900 mcg of vitamin A, 90 mg of vitamin C, and 15 mg α-tocopherol through a balanced diet is sufficient to support antioxidant defenses [ 206 , 207 ], with targeted supplementation reserved for those with demonstrated inadequacies, increased oxidative stress, or specific clinical indications.

A comprehensive PubMed and Scopus search identified articles linking physiological effects of environmental EDCs with mitigating effect of AVs. Key words included “environmental exposure and antioxidant vitamins” and “endocrine disruptors and antioxidant vitamins.” Two authors (S.V.T., C.O.) independently screened eligible articles with the following criteria: (1) human or animal subjects; (2) involvement of both environmental exposures and vitamins, with an association between the two; and (3) full text available in English. Exclusion criteria were (1) in vitro experiments; and (2) reports, letters, and reviews. Full texts of articles published from January 2000 to August 2025 were reviewed for inclusion.

Bisphenols are a class of widely used industrial chemical found in plastics and epoxy resins that has raised substantial public health concerns due to its endocrine-disrupting properties. Among these, bisphenol A (BPA) is the most extensively studied, although alternatives such as bisphenol S and bisphenol F are increasingly drawing attention. BPA is ubiquitously present in consumables such as epoxy-lined cans and containers, tableware, and water bottles made from polycarbonate; prolonged storage or heat exposure can facilitate its leaching into food and increase human exposure. Exposure to BPA has been linked to reproductive toxicity, metabolic disturbances, neurodevelopmental abnormalities, and increased risk of cancers, largely through its ability to mimic or interfere with natural hormone signaling pathways [ 62 ]. Animal studies exploring the potential of vitamins to counteract the endocrine-disrupting effect of BPA (summarized in Table 1 ) on reproductive toxicity both in males and females have been reviewed earlier [ 63 , 64 ]. Effect of antioxidant vitamins on health effects from bisphenol A exposure in animals Abbreviation: BPA, bisphenol A. These studies found that vitamin A treatment counteracted BPA toxicity, by inhibiting the BPA-induced toxicity in the liver, uterine weight increase in ovariectomized rats [ 65 ], and prevented sperm motility decrease in mice [ 66 ]. Vitamin C had sex- and organ-specific effects in rats exposed to BPA. In male rats, vitamin C increased oxidative damage in the kidney following long-term BPA exposure [ 67 ], whereas it mitigated adverse changes in epididymal sperm and epididymis in male rats [ 68 ], and ovarian and oocyte morphology in female rats [ 69 ]. Vitamin E, on the other hand, demonstrated protective effects in both sexes: It minimized BPA-induced impairments in blood lipid peroxidation, sperm motility, and testicular tissue in male rats [ 70 , 71 ], and prevented lipid peroxidation in the liver, kidney, and ovary of female rats [ 72 , 73 ]. The combination of vitamins C and E also mitigated the effect of high doses of BPA on ovarian cell death [ 74 ]. Despite promising in vivo results, there is a lack of human studies on the effect of AVs in reducing BPA toxicity. Further research in human populations is needed to determine whether antioxidant supplementation can effectively mitigate BPA's adverse health effects. Phthalates are synthetic chemicals widely used as plasticizers in a variety of consumer products such as vinyl flooring, food packaging, personal care items, and medical devices. Due to their endocrine-disrupting properties, phthalate exposure has been linked to reproductive toxicity, neurodevelopmental impairment, metabolic disorders, and a higher risk of chronic diseases, primarily through disruption of hormone signaling [ 75 ]. Comprehensive reviews have found that AVs mitigated the adverse effects of phthalate exposure on reproductive and neurological toxicity, metabolic disruptions, spleen and kidney injury, as well as cardiopulmonary dysfunction [ 76 , 77 ]. While epidemiological studies demonstrated that dietary intake of vitamin A mitigated the phthalate-induced biological aging [ 78 ] and phthalate-induced insulin resistance [ 79 ], there is a notable lack of animal studies investigating the mechanisms and overall effect of vitamin A supplementation. Animal studies on vitamin C treatment showed conflicting results with reduced oxidative stress and alleviated thyroiditis in female rats [ 80 ], but in male rats with prenatal exposure to phthalate, there was no protective effect and even exacerbated oxidative stress or reproductive harm [ 81 ]. Vitamin E conferred resistance to testicular toxicity, reproductive malformations, and adverse testicular histology from early developmental exposure to phthalate [ 82 ], indicating the important role of the mother's nutrition intake on offspring development. Its protective effects extended to the liver, kidneys [ 83 ], and even depressive symptoms from combined phthalate and ozone prenatal exposure [ 84 ]. Combined with salidroside, vitamin E also countered cardiofibrotic and endocrine effects of phthalate [ 85 ]. Coadministration of vitamins C and E consistently reduced phthalate-induced testicular injury and spermatogenic dysfunction in male rats [ 86 ], promoted regeneration of seminiferous epithelium in mice [ 87 ], and protected against lipid peroxidation, impaired insulin signaling, and oxidative damage in skeletal muscle and adipose tissue [ 88 , 89 ]. Collectively, these findings (animal studies summarized in Table 2 and epidemiological studies summarized in Supplementary Table S1 [ 90 ]) suggest that combined vitamin C and E supplementation offers the most reliable protection against phthalate toxicity, particularly for male reproductive health and oxidative balance. Variability in outcomes highlights the need for targeted antioxidant strategies based on exposure timing, toxicant, sex, and supplement combinations. Effect of antioxidant vitamins on health effects from phthalate exposure in animals Abbreviations: GD, gestational day; PND, postnatal day. Pesticides include a diverse group of chemicals extensively used in agriculture to control pests and increase crop yields. However, many pesticides act by interfering with cellular signaling pathways and can accumulate in the environment and the human body, raising concerns about long-term health effects. Exposure to pesticides is associated with numerous detrimental health effects, including neurotoxicity, reproductive harm, endocrine disruption, and increased risk of cancers [ 94 ]. Experimental studies across diverse animal models consistently demonstrated the protective effects of AVs against pesticide-induced oxidative stress ( Table 3 ). Vitamin C supplementation in catfish and Nile tilapia effectively mitigated metabolic disturbances [ 95 ] and attenuated oxidative damage in vital organs like the brain and liver following exposure to pesticides such as deltamethrin, cypermethrin, and chlorpyrifos [ 96 ]. Effect of antioxidant vitamins on health effects from pesticide exposure in animals Abbreviations: GD, gestational day; MDA, malondialdehyde; PND, postnatal day; ROS, reactive oxygen species. These changes are indicative of improved physiological resilience in response to AV intake. However, the effectiveness of antioxidants is not uniform across all species. In zebrafish embryos, vitamin C administration reduced butachlor-induced mortality and oxidative markers [ 99 ] but offered limited protection against chlorpyrifos-induced oxidative stress [ 98 ], likely a function of toxicant-dependent variability in efficacy, since both exposures involved identical exposure windows in the same species. Vitamin E on the other hand showed benefits, restored redox balance, and organ function in pesticide-exposed catfish [ 102 ], and improved immune responses in amphibian models exposed to atrazine when combined with β-carotene [ 106 ]. In rodent studies, vitamins E and C, alone or in combination with other antioxidants (such as selenium or curcumin), reduced oxidative stress, prevented genotoxicity, and protected against reproductive and neurodevelopmental toxicity following exposure to organophosphates, pyrethroids, and other pesticides [ 100 , 101 , 105 , 109 ]. Additionally, vitamins E and C protected male and female mouse offspring, prenatally exposed to mancozeb, from ovarian and testicular tissue dysfunction [ 107 , 108 ], highlighting their efficacy in mitigating reproductive toxicity associated with in utero exposure. While animal studies have consistently reported a protective effect of vitamin E against pesticide-induced health effects, there is a notable lack of epidemiological studies evaluating the effect of AVs on pesticide-associated health outcomes, which needs further evaluation. Persistent organic pollutants (POPs) are a class of toxic chemicals that resist environmental degradation and can accumulate in the food chain. Due to their persistence and bioaccumulative properties, POPs have been linked to a range of adverse health effects, including immune system suppression, reproductive and developmental toxicity, endocrine disruption, and an increased risk of cancer [ 110 ]. The limited studies exploring the effect of AVs on physiological effects from POPs have shown beneficial effects ( Table 4 ). Vitamin E coadministration showed a protective effect on POP-induced testicular disruptions and oxidative stress in male rats [ 111 , 112 ] and oxidative stress in the female rat brain [ 113 ]. Effect of antioxidant vitamins on health effects from persistent organic pollutant exposure in animals Abbreviation: POP, persistent organic pollutant. In contrast, investigations using zebrafish embryos suggested a more selective benefit. Vitamin E supplementation reduced polycyclic aromatic hydrocarbon (PAH)-induced locomotor dysfunction [ 114 ] and polychlorinated biphenyl (PCB)-induced embryotoxicity [ 115 ] but conferred minimal protection against PCB-associated cardiovascular impairments [ 116 ]. Studies examining the protective effects of vitamins C and E against PCB exposure in rats demonstrated significant mitigation of oxidative stress in various tissues, including the liver, kidney, lungs, in addition to improving Leydig cell function, and femoral bone metabolism [ 117-119 ]. Epidemiological studies demonstrated mostly protective effects of AVs on POP-induced effects. Studies in pregnant women showed vitamin C decreased the levels of PCB and oxidative stress in blood [ 120 ] and reduced adverse effects of PAH on birthweight [ 121 ]. Vitamin E showed a protective effect on PAH-exposure–induced DNA adducts in cord blood and protected blood pressure but not behavioral changes in children [ 122-124 ]. Similarly, a large cohort study found serum carotenoid level to be associated with reduced probability of dioxin-like PCB-associated risk for type 2 diabetes [ 125 ]. Dietary vitamin A, C, E, folate, and carotene intake reduced the risk of preterm birth associated with PAH exposure [ 126 ]. However, one cohort study showed no effect of any of the AVs (A, C, and E) on PAH-exposure–induced DNA adducts [ 127 ]. Overall, evidence both from animal and epidemiological studies (summarized in Supplementary Table S1 [ 90 ]) suggests that AVs may mitigate a variety of POP-induced adverse health effects, though their protective efficacy appears to vary by pollutant type, exposure outcome, and population, highlighting the need for further research to clarify their mechanisms and consistency of benefit. Smoking, including the use of cigarettes and other tobacco products, is a leading preventable cause of morbidity and mortality worldwide [ 128 ]. Tobacco smoke is known to carry several toxic chemicals, including nicotine, tar, carbon monoxide, formaldehyde, benzene, and heavy metals. It is associated with a wide range of detrimental health effects, including increased risk of cardiovascular disease, respiratory illnesses such as chronic obstructive pulmonary disease and lung cancer, reproductive harm, and impaired immune function [ 129 ]. Coadministration of vitamin C mitigated memory deficits and restored hippocampal antioxidant activity in male rats exposed to tobacco smoke [ 130 ]. Vitamin C also ameliorated nicotine-induced impairments in placental development and hemodynamics in pregnant rhesus macaques, offering prenatal benefits [ 131 ]. However, in rats exposed to perinatal smoking, vitamin C neither improved birthweight or oxidative stress markers nor protected against postnatal pulmonary dysfunction; notably, its subcutaneous administration even had negative, pro-oxidant effects [ 132 , 133 ]. Vitamin E demonstrated broader protective effects, particularly in male rats, in which it prevented smoking-induced memory impairment, normalized oxidative stress biomarkers, improved testicular histology and function, and restored reproductive hormone levels [ 134 , 135 ]. In male mice, vitamin E provided only partial benefits for learning and memory deficits associated with pregestational tobacco smoke exposure, highlighting species-specific differences in efficacy during prenatal nicotine exposure [ 126 ]. In humans, short-term vitamin C exposure improved endothelial dysfunction in male smokers [ 136 ] while combined vitamin C and E supplementation resulted in a 31% reduction in DNA damage markers in female but not male smokers [ 137 ]. Collectively, these findings (animal studies summarized in Table 5 and epidemiological studies summarized in Supplementary Table S1 [ 90 ]) suggest that vitamins C and E can provide neuroprotective and systemic benefits against certain deleterious effects of tobacco and nicotine, although their efficacy can be tissue, species, or outcome specific and may be influenced by the timing and duration of exposure. Effect of antioxidant vitamins on health effects from tobacco exposure in animals Abbreviations: GD, gestational day; N/A, not available; PND, postnatal day. PM comprising tiny solid particles and liquid droplets suspended in the air, originate from vehicle emissions, industrial activity, construction, wildfires, and dust storms. Due to their small size, fine particles (PM2.5) can penetrate deep into the lungs and enter the bloodstream, thereby intensifying their adverse health effects including increased risk of respiratory and cardiovascular diseases, asthma exacerbation, impaired lung development, and increased mortality risk [ 139 ]. Several vitamins have shown mitigating effects against PM-induced changes in animal and human studies (see Supplementary Table S1 [ 90 ]). Comprehensive reviews have discussed how vitamins modulate the adverse impacts of traffic-related air pollution [ 140 ] and the cardiopulmonary toxic effects of air pollution [ 141 , 142 ]. In zebrafish, vitamins C and B9 showed a synergistic inhibitory effect on PM-induced apoptosis and heart defects [ 143 ]. In rats, coadministration of vitamin E reduced pulmonary dysfunction markers following exposure to gas exhaust particles [ 144 ]. Interventional and observational studies on respiratory health in humans have provided mixed findings. Randomized controlled trials found that vitamin C supplements did not improve blood pressure or vascular function in adults exposed to PM and ozone [ 145 ], while a similar trial showed vitamin C and N-acetylcysteine pretreatment increased vasoconstriction in adults exposed to diesel exhaust particles [ 146 ]. However, several other studies showed positive effects of vitamin C. In a UK study on asthma patients, vitamin C, and to a lesser extent, vitamin E but not vitamin A, attenuated PM10-induced exacerbations in asthma patients [ 147 ]. Similarly, in India, higher intakes of vitamins C and D correlated with lower acute respiratory illness risk, while a combined intake of vitamins A, C, D, zinc, and selenium reduced anemia risk related to pollution exposure [ 148 ]. In children with moderate asthma, vitamins C and E protected against acute ozone-induced lung function decline [ 149 ]. Evidence from cohort studies has highlighted the potential of dietary antioxidant intake to mitigate the harmful health effects associated with air pollutant exposure. A large Spanish cohort study found that adverse effects of prenatal air pollutant exposure on infant mental development were more pronounced in infants of mothers with low AV intake during pregnancy, implying a protective role for maternal intake [ 150 ]. In Chinese cohorts, a higher AV intake was associated with improved ovarian cancer prognosis in individuals exposed to PM [ 151 ]. Sufficient dietary AV intake also reduced diabetes risk from air pollution in a large British cohort [ 152 ]. Conversely, a few studies have reported limited or no benefits. In children exposed to PM, there was no significant relationship between AV intake and respiratory symptoms or pulmonary function [ 59 , 153 ]. Similarly, in adults, there was no link between short-term PM exposure, cardiometabolic disease incidence, and dietary AV intake [ 154 ]. Overall, the majority of studies indicate that AVs offer protective benefits against the adverse effects of air pollution, particularly in vulnerable populations or those with low baseline intake. However, the protective effects were not consistently observed across all studies or health end points. This inconsistency highlights that factors such as dose, timing, population characteristics, and the specific health outcomes assessed are critical determinants of AV efficacy. Heavy metals are prevalent environmental endocrine disruptors, commonly originating from industrial emissions, occupational exposures, contaminated food, and water. Chronic exposure to heavy metals is linked to hormonal imbalances contributing to increased risk of reproductive, developmental, metabolic, and neurobehavioral disorders [ 155 ]. A large body of work has explored the mitigating potential of AVs on heavy metal exposure with protective effects being found on male reproduction, the liver, and brain [ 156-158 ]. Comprehensive reviews on AVs mitigating adverse health effects from exposure to cadmium [ 159 ], chromium [ 160 ], arsenic [ 161 ], and lead [ 162 , 163 ] are already available. Therefore, these topics are summarized in Supplementary Table S2 [ 90 ] rather than discussed in detail. Briefly, current evidence suggests that vitamins C and E frequently mitigated the toxic effects of heavy metals such as cadmium, lead, mercury, arsenic, chromium, and aluminum across various animal models. These AVs reduce oxidative stress and organ damage, and restore biochemical and reproductive functions disrupted by metal exposures, although the magnitude and consistency of protective effects varied by metal type, nutrient combination, exposure duration, and model organism. Notably, studies often lacked uniformity in dosing, assessment end points, and consideration of baseline nutritional status, highlighting gaps in translating these findings to human populations. Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals present in fire-retardants, oil-/water-repellant textiles, nonstick cookware, and food packaging material. They are detected in nearly 98% of the population and are linked to adverse health outcomes including metabolic disorders and cancer [ 164 , 165 ]. Although preliminary research suggests that AVs may offer protective effects against PFAS toxicity, the available literature remains limited. Animal studies have demonstrated a protective role of vitamin C against perfluorooctanoic acid– and perfluorooctanesulfonic acid (PFOS)-induced toxicity in the liver [ 166 , 167 ] and spleen [ 168 ]. In humans, vitamin C intake was associated with reduced insulin resistance from PFOS and perfluorododecanoic acid exposure in an older population [ 169 ]. There is also evidence that PFAS disrupts vitamin A and E metabolism; however, the biological consequences and the potential protective role of vitamins A and E require further investigation [ 170 ].

Preliminary evidence suggests that vitamins C and E may protect against adverse health effects from environmental exposures. Advancing this field on gene-environment-nutrition interaction will require standardized vitamin and exposure assessments, precise timing and dosage considerations, integrated dietary and biomarker analyses, and inclusion of nutrigenomic data. Until more definitive evidence emerges, increasing consumption of fresh, minimally processed, vitamin-rich food remains a prudent strategy to mitigate environmental health risks.

In a healthy cell, the excess ROS and other free radicals are scavenged by the body's natural antioxidant defense system that includes (i) enzymatic antioxidants like catalase, superoxide dismutase, thioredoxin, peroxiredoxin, and glutathione transferase, and (ii) nonenzymatic antioxidants like vitamins A, C, and E, melatonin, ubiquinone, flavonoids, uric acid, and glutathione [ 49 ]. This review focuses on the well-established primary AVs—vitamin A (retinol and its derivatives) and its precursors (carotenoids), vitamin C (ascorbic acid), and vitamin E (α-tocopherol). Other vitamins, such as B12, D, and K, which function as coenzymes or regulators that support the antioxidant machinery indirectly, have been excluded from this review. Vitamin A scavenges peroxyl radicals in the cytoplasmic lipid phase [ 50 ], while vitamin E, a membrane-located lipophilic antioxidant, is a peroxyl radical scavenger that breaks the chain reaction of lipid peroxidation [ 51 , 52 ]. Vitamin C directly scavenges free radicals in the aqueous phase and suppress their generation by inhibiting NADPH oxidase activity and mitigating mitochondrial electron transport-chain deficiencies. Additionally, vitamin C interacts synergistically with other exogenous antioxidants like polyphenols and helps regenerate vitamin E, thereby enhancing the overall cellular antioxidant activity and reduces oxidative stress damage by repairing DNA damage [ 53 ]. The detailed mechanisms of action of these antioxidant molecules are discussed elsewhere [ 54 ]. AVs are readily available in the diet, particularly in fruits, vegetables, and seeds [ 55 ]. Vitamin A is found in animal foods like liver, dairy, and eggs (as retinol), and in plants such as leafy greens and orange vegetables (as carotenoids). Citrus fruits, berries, peppers, and cruciferous vegetables are major sources of vitamin C. Vitamin E is abundant in vegetable oils, nuts, seeds, and whole grains. Beyond natural sources, these vitamins are also provided through fortified foods (cereals, milk, juices) and supplements, which significantly contribute to intake in the general population [ 56 , 57 ]. Incorporating AV-rich foods can effectively enhance the body's defenses against environmentally induced oxidative stress. This is particularly relevant since several animal and human studies have demonstrated reduced plasma levels of vitamins A, C, and E following exposure to environmental chemicals like perfluoroalkyl and polyfluoroalkyl substances, PM and heavy metals [ 58-61 ].

A wide range of environmental toxicants including heavy metals (lead, mercury, cadmium, chromium, arsenic), plasticizers (phthalates, bisphenols), air pollutants (ozone, particulate matter [PM]), and persistent organic pollutants (dioxins, polychlorinated biphenyls) have now become pervasive. Humans are exposed to these predominantly through ingestion, inhalation, and skin contact, leading to accumulation of these toxicants in circulation and tissues, causing cellular damage [ 37 , 38 ]. Environmental toxicants are known to increase the production of ROS, such as superoxide anion, hydrogen peroxide, and hydroxyl radicals, disrupting cellular function [ 39-42 ]. These exposures can increase ROS levels directly through redox-active groups in some metals and pollutants, or indirectly by disrupting mitochondrial function, triggering redox cycling, or activating enzymes like NADPH oxidase [ 43 , 44 ]. Oxidative stress arises when ROS production exceeds the neutralizing capacity of endogenous antioxidants, resulting in redox imbalance, which in turn triggers widespread molecular damage. This includes lipid peroxidation that harms cellular membranes and signaling, protein oxidation that impairs enzyme function and structure, and ROS-induced DNA lesions such as strand breaks, base modifications, and cross-linking, leading to mutagenesis and genomic instability [ 45 , 46 ]. Accumulation of these damages disrupts cellular function, triggers apoptosis, and ultimately contributes to tissue and organ dysfunction, leading to several diseases. Given the importance of ROS as signaling molecules, it is essential to limit exposure to environmental toxicants known to induce excessive ROS production [ 47 , 48 ].