There are a number of viable technology options for low-carbon electricity supply. Consequently, there is much more flexibility in decarbonizing the power sector than nonelectric energy supply5. For instance, some low-carbon electricity pathways rely heavily on nuclear or carbon capture and storage (CCS), while others focus mostly on renewable energy sources5,34. This is reflected in the scenario set considered here: In addition to a Full Technology climate change mitigation scenario (FullTech), we consider two more mitigation scenarios with either a Conventional Technology portfolio (combined share of wind and solar power restricted to 10%&#;Conv, in line with assumptions in other IAM studies that explored techno-economic impacts of technology constraints6,35,36), or a New Renewables portfolio (nuclear phase-out, no CCS deployment in the power sector&#;NewRE) to contrast the implications of opposing mitigation strategies. Moreover, considering a baseline scenario Base without emissions constraint establishes a reference point against which we can evaluate co-benefits and adverse side-effects of power sector decarbonization (Table 1). The resulting electricity generation mixes for the four scenarios and five participating IAMs are shown in Fig. 1 and available in Supplementary Data 1.
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Table 1 Overview of scenarios consideredFull size table
Fig. 1Scenarios of future electricity generation. Projections of electricity generation for the baseline and three decarbonization scenarios compatible with limiting warming to well below 2&#;°C, as modeled by five structurally different Integrated Assessment Modeling systems
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The energy sector poses health risks due to emissions of air, water, and soil pollutants, in addition to those of greenhouse gases. Our analysis framework allows us to contrast these impacts for the four transformation scenarios and to attribute them to specific technologies. It should be noted that the life-cycle assessment approach limits our evaluation to normal operation only, which means that impacts from exceptional events (e.g. dam failures, mining accidents, pipeline explosions, or nuclear meltdowns) are excluded from this analysis.
The power sector is one of the major sources of air pollutant emissions, and air pollution is a major threat to human health37. In , the power sector accounted for around 40% for global SO2 emissions, and 20% of NOx38. These substances are important precursors for particulate matter formation (PM-10) (Fig. 2a). NOx, along with CH4 and other volatile organic compounds (NMVOCs), also enhance photochemical oxidant formation, i.e., tropospheric ozone (Fig. 2b). In particular PM-10 but also tropospheric ozone are important health threats39. In line with previous studies8,17, we here find that air pollutant emissions and concentrations stabilize or decrease slightly even with a massive upscaling of fossil-based power production in absence of climate policies (Fig. 2a). This is largely due to increasing regulation and end-of-pipe measures to control pollution8,40 and follows the historical trend in industrialized countries38. The power sector&#;s contribution to PM-10 and ozone originates almost exclusively from the combustion of fossil fuels and bioenergy (Fig. 2a, b). Our analysis also accounts for upstream emissions due to indirect energy demands for the construction of energy conversion technologies, fuel production and handling. However, we find that upstream fossil fuel use25 and indirect air pollution associated with noncombustion power technologies are rather small compared to direct emissions (see Supplementary Fig. 1).
Fig. 2Environmental impacts affecting human health. Globally aggregate environmental impacts from a particulate matter formation, b photochemical oxidant formation, c human toxicity, and d ionizing radiation, in and under different power sector transformation scenarios. Stacked bars indicate mean across all combinations for LCA technology variants and IAM scenario realizations. Boxplots indicate median and interquartile ranges across technology variants and participating integrated assessment models, whiskers 10th&#;90th percentile ranges. Ranges do not reflect uncertainty in environmental impact characterization. Base Grid refers to generic grid requirements determined by total electricity demand, while VRE grid refers to additional grid requirements for coping with the variability of renewable electricity supply from wind and solar power
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Climate change mitigation lowers air pollution drastically and more so in the NewRE than in Conv scenarios. On average across models, the decline of fossil-based power in NewRE climate policy results in reductions of 87% and 83% of PM-10 and ozone precursors, respectively, relative to the baseline case. Air pollution impacts in the Conv case are around double of those in the NewRE case, largely due to greater remaining direct NOx emissions as well as higher indirect air pollution from upstream energy requirements for the extraction and handling of fossil fuels. This is despite strong co-control of sulfur in CCS plants (Fig. 3, Supplementary Fig. 2 and ref. 41).
Fig. 3Selected technology-specific environmental impacts. Per unit life-cycle impacts of electricity technologies for the FullTech scenario and the year for impact indicators dominating the endpoints human health, ecosystem damages and resource depletion. Boxplots indicate median and interquartile ranges across technology variants and participating integrated assessment models, whiskers 10th&#;90th percentile ranges. Ranges do not reflect uncertainty in environmental impact characterization. The full set of indicators is displayed in Supplementary Fig. 2
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All energy technologies cause human toxicity impacts due to chemical toxicant emissions in their supply chains, albeit at different scales (Fig. 2c). They are particularly high for coal (leaching of toxicants from mine dumps), bioenergy (agrochemicals use in agriculture), and still significant for gas (emissions during natural gas extraction), nuclear (tailings from uranium mining and milling) and photovoltaics (emissions from copper processing and silicon refinement). Overall, a pattern similar to air pollution impacts emerges: human toxicity is strongly reduced under climate policies, and around 60% lower in NewRE compared to Conv.
Another relevant impact from the power sector stems from the ionizing radiation emitted by radioactive substances (Fig. 2d). Ionizing radiation is almost exclusively caused by nuclear power, and dominated by releases from mining and milling during the production of nuclear fuels. Per-unit impacts for all other technologies, including coal power, are more than two orders of magnitude smaller (see Supplementary Fig. 2) and largely due to upstream nuclear power use. Importantly, LCA inventories and assessment methods do not account for the risk of radiation exposure nuclear accidents42. However, analysis by Hirschberg et al.43 and others44,45 suggest first that, in terms of lost life years, fatalities from accidents tend to be considerably smaller than health impacts from regular operation, and second that fatalities from nuclear accidents tend to be lower than those from fossil-based or hydropower.
In the absence of climate policies, models project an increase of around 50% nuclear power use by , resulting in a corresponding rise in related radiation impacts. Climate change mitigation could result in a further expansion of nuclear power and corresponding radiation impacts by a factor of 3&#;7 in the FullTech scenarios relative to , or even 5&#;8 if the use of wind and solar power is limited (Conv scenarios). In the NewRE scenarios, by contrast, ionizing radiation impacts are limited to the extent that pre-existing nuclear power plants are phased out of power supply. The analysis of endpoint impacts indicates that ionizing radiation contributes less to human health impacts than particulate matter, ozone, or other toxic pollution (combined assessment section).
The power sector also threatens the health of ecosystems. Relevant impact channels include land occupation and transformation, as well as pollutant release resulting in terrestrial acidification, eutrophication and ecotoxicity impacts.
Land-use for agricultural and other human activities is a crucial driver of global biodiversity loss and degradation of many ecosystem services46. In , the land footprint attributable to power supply compared to around 12% of total built-up area47. The ReCiPe LCIA differentiates between land occupation of areas already transformed from its natural state, and natural land transformation, e.g. from forests to croplands. Natural land transformation accounts for the quality of the land being transformed, putting particular emphasis on reduction of biodiversity-rich forest areas. In all scenarios considered, both land occupation (Fig. 4a) and natural land transformation (Fig. 4b) for power supply will increase in the future relative to current level. In Base, the power sector&#;s land-use increases due to an increase of the power system&#;s scale and is largely attributable to coal (both area occupied by open-cast coal mines, and land-use associated with timber used for the support of underground mines), biomass and hydropower (land-use for reservoirs). We find that climate policy tends to increase power-system related pressure on land, largely because of increasing biomass use. On a per-MWh basis, electricity from biomass with CCS is more than 20 times more land-intensive than hydropower, coal with CCS, or CSP, and exceeds wind and PV by around two orders of magnitude (Fig. 3). Due to the deforestation induced by biomass expansion, bioenergy figures even more prominently in natural land transformation impacts. Overall, bioenergy-induced land-use impacts tend to be greatest in the Conv scenarios, as negative emissions from BECCS are required to compensate for residual CO2 from imperfect carbon capture in fossil CCS plants. Importantly, however, we find very high uncertainty&#;i.e., technology, policy and management dependence&#;in the ecosystem impacts form land-use, with the variability induced by management practices and IAM model uncertainty exceeding the differences across scenarios (Supplementary Fig. 3). In comparing fossil to nonfossil power generation, it is also important to emphasize that our analysis does not account for habitat losses caused by coastal flooding. Due to higher climate change-induced sea level rise, coastal flooding will be more severe in the Base scenario than in the climate change mitigation scenarios.
Fig. 4Environmental impacts affecting ecosystems. Globally aggregate environmental impacts from a land occupation, b natural land transformation, c terrestrial acidification, d freshwater ecotoxicity, as well as e marine and f freshwater eutrophication, as well as g water withdrawal, for and under different power sector transformation scenarios. Ecotoxicity was calculated as the aggregate of terrestrial, marine and freshwater ecotoxicity in units of species-years using characterization factors from ref. 23. Stacked bars indicate mean across all combinations for LCA studies and IAM scenario realizations. Boxplots indicate median and interquartile ranges across technology variants and participating integrated assessment models, whiskers 10th&#;90th percentile ranges. Ranges do not reflect uncertainty in environmental impact characterization
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Another important factor for the land footprint of electricity supply systems is the grid infrastructure for transmission and distribution, which accounts for around one third of the total. As an expansion of grid interconnectors is an important option for coping with the variability of wind and solar power supply48, we here account explicitly for the dependence of transmissions grid requirements on the generation share of wind and solar (see Methods). However, we find that the land occupation attributable to additional grid requirements for wind and solar integration is small compared to the land footprint from the general electricity grid.
Further ecosystem damage is inflicted from the release of various chemical substances. Atmospheric sulfur and nitrogen oxides from combustion result in terrestrial acidification. In line with the reduction of health impacts from air pollution, terrestrial acidification is projected to decline slightly under the baseline scenario, and to fall to less than a fifth of current levels by under 2&#;°C-consistent stabilization (Fig. 4c). Similar to toxicants harmful to humans, all technologies feature life-cycle ecotoxicity impacts (Fig. 4d). However, on a per-MWh basis, these are greatest for fossil technologies (emissions during extraction), substantial for bioenergy (agrochemicals use for crops), and much smaller for wind and solar (Supplementary Fig. 2). As a consequence, ecotoxicity impacts in the NewRE decarbonization scenarios are around 30% lower than those in FullTech. As the Conv scenarios rely more heavily on natural gas with CCS, ecotoxicity impacts are 25% greater than in FullTech, and on average around double those estimated for .
Another relevant channel for ecosystem impacts are marine and freshwater eutrophication (Fig. 4e, f). The leaching of phosphate from coal production is the dominant contributor to freshwater eutrophication impacts, as ReCiPe assumes phosphate to be the primary limiting nutrient for freshwater ecosystems23. In contrast to freshwater, nitrates induce a higher eutrophication response for marine ecosystems23,49. Emissions of nitrogen oxides from combustions as well as direct nitrate releases from fertilizers for bioenergy cultivation therefore contribute to marine eutrophication. For both freshwater and marine eutrophication, the strong reduction of fossil fuel use results in substantial decreases in mitigation scenarios compared to Base. These co-benefits are greatest for the NewRE scenarios.
Not only the contamination of water with chemical substances, but also its withdrawal from river systems is an important environmental stressor. Electricity supply systems account for approximately 14% of global human water withdrawal13: Most thermal power plants use water for cooling, while hydroelectric plants affect waterways through dams and water losses to evaporation and seeping50,51. As discussed in earlier literature11,12,20,50,51, future projections of water withdrawals are highly uncertain as they depend on the degree to which utilities adapt to water scarcity, for instance by installing dry cooling technologies in thermal power plants. Besides cooling water, water losses from hydropower and withdrawals for biomass irrigation are projected to increase substantially in the future21. Across decarbonization scenarios, water withdrawal is highest in the Conv scenarios due to the large share of nuclear power, which is particularly cooling-water-intensive (Fig. 4g). The NewRE scenarios, by contrast, have very little thermoelectric capacities, and thus features distinctly lower water withdrawals than the Conv and FullTech scenarios.
Beyond damages to human health and ecosystems, the energy sector also contributes strongly to the depletion of exhaustible resources, thus reducing natural capital and options for future generations. It is important to keep in mind that the health and ecosystem damage associated with resource extraction are already accounted for in the other impact indicators, such as ecotoxicity or human toxicity.
In absence of climate policies, fossil depletion is projected to roughly double by mid-century relative to levels, as supply-side efficiency improvements and the contributions of renewables and nuclear are insufficient to offset strongly increasing electricity demand (Fig. 5a). Climate policy does not necessarily reduce fossil depletion, as gas with CCS becomes increasingly important and replaces coal. In the Conv and FullTech cases, around half the models project fossil use for power supply to exceed levels. In NewRE case, by contrast, the models project on average an around 75% reduction of fossil depletion relative to levels. Natural gas used to provide flexible backup power compensating fluctuations from wind and solar electricity accounts for most of the remaining fossils in these NewRE scenarios. Indirect fossil energy requirements for power supply, e.g., manufacturing of solar panels, are fully accounted for in our analysis but found to be relatively small even in the NewRE scenario.
Fig. 5Resource impacts. Globally aggregate resource impacts from a fossil depletion, b mineral resource depletion, and c geological CO2 storage requirements, for and under different power sector transformation scenarios. Stacked bars indicate mean across all combinations for LCA studies and IAM scenario realizations. Boxplots indicate median and interquartile ranges across technology variants and participating integrated assessment models, whiskers 10th&#;90th percentile ranges. Ranges do not reflect uncertainty in environmental impact characterization
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In the FullTech and Conv scenarios, the continued use of fossils can only be reconciled with the tight emissions constraints via carbon capture and storage (CCS). This gives rise to geological CO2 storage as a new exhaustible resource depleted by the energy sector. Our results indicate that the power sector would account for around 11 [4&#;16] GtCO2/yr storage requirements in FullTech, and 15 [10&#;21] GtCO2 in the Conv scenarios (Fig. 5c) by , which increases further in the majority of model simulations thereafter (Supplementary Fig. 4). The power sector competes with other potentially important CCS use cases, such as biomass with CCS for nonelectric fuels, CCS for industry, or direct air capture. While currently available estimates suggest a total geological technical potential for CO2 storage of at least ~&#;GtCO252, economically and societally acceptable CO2 storage potentials are likely to be much more limited.
Power supply also accounts for a substantial share of mineral resource depletion, mostly for the construction of power generators. In , around 5% of global copper, 2.5% of aluminum, and 3% of iron went into the electricity supply sector53. Mineral resource depletion accounts for the aggregate demands from these bulk metal demands along with some 20 other important mineral resources. It should be noted that concerns about mineral resource depletion involve a large number of minerals, not all of which are covered by life-cycle impact assessment methods. For example, the indicator used here does not include neodymium or dysprosium (used in certain wind turbines54), or indium or tellurium (used in certain photovoltaic cells)54. In all scenarios, nonfuel mineral depletion increases relative to current levels. In contrast to all other indicators we find that all climate policy scenarios feature higher mineral resource requirements, and that in the NewRE scenarios mineral resource depletion is around twice as high as in FullTech, and around four times higher than in the baseline (Fig. 5b). This is explained, first, by the higher per-unit metal requirements for renewable technologies, particularly solar PV; second, the fact that wind and solar technologies require substantial material upfront investments before operation (which here are attributed to the year of construction); and finally, to a lesser extent, the additional metal resources required for the build-up of additional grid and storage infrastructure to accommodate the variability of wind and solar power supply.
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The comparison of differences across scenarios demonstrates that electricity decarbonization has substantial nonclimate co-benefits for most environmental impacts at the midpoint level of the cause-effect chain (Fig. 6a), as well as the human health and resource depletion impacts at the endpoint level (Fig. 6b&#;d). However, some environmental pressures induced by power supply emerge as crucial concerns, as they are likely to increase in the future and might be exacerbated by the low-carbon transformation: first, land requirements; second, mineral resource depletion; and third, impacts related to the use of radioactive materials, not only ionizing radiation as considered here, but also the risk of nuclear accidents and the production of nuclear waste.
Fig. 6Combined assessment of global environmental impacts of alternative decarbonization strategies in . a Relative size of midpoint environmental impacts for conventional (Conv scenarios) vs. new renewable-based (NewRE scenarios) strategies, compared to those that would have occurred in absence of climate policies (Base scenario), on a logarithmic scale. Aggregate endpoint impacts by (midpoint) impact channel: b human health damages in disability-adjusted life-years lost, c ecosystem damage in species-years, and d surplus costs from exhaustible resource depletion. Shaded ranges in (a) as well as boxplots in (b&#;d) indicate interquartile ranges across IAMs and LCA technology variants, whiskers in (a&#;d) indicate 10th&#;90th percentile range. Ranges do not reflect uncertainty in environmental impact characterization. Note that oxidant formation, freshwater eutrophication, ecotoxicity and terrestrial acidification impacts account for a below 2% share in total endpoint impacts, and are therefore barely visible
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We further find that different decarbonization strategies result in distinctly different profiles of risks and co-benefits. Wind and solar-based decarbonization (NewRE scenario) consistently achieves highest reductions in health-related environmental impacts (Fig. 6b). Fossil technologies&#;especially coal&#;dominate aggregate health impacts by far (see Supplementary Fig. 5); thus, their faster and deeper phase-out in the NewRE scenarios yields greatest benefits, with around 60% lower aggregate mortality compared to Conv, and an around 50% decrease relative to FullTech in . The most prominent contributors to health impacts are air pollution and human toxicity.
NewRE decarbonization also minimizes pollution-related ecosystem impacts compared to Conv and FullTech scenarios. Aggregate ecosystem damage, as derived from the corresponding ReCiPe endpoint characterization factors23, are dominated by land occupation and natural land transformation. These land-use related impacts are highly uncertain and of comparable magnitude across the different decarbonization scenarios: While NewRE scenarios are characterized by greater land-requirements for wind and solar power as well as grid expansion, the higher bioenergy deployment in the Conv scenarios induces greater natural land transformation (Fig. 6c and Supplementary Fig. 5).
We also find that decarbonization will fundamentally change the resource requirements of the power sector, away from fossil fuel inputs and towards mineral resources (FullTech and NewRE) and geological storage space for CO2 (FullTech and Conv). For the NewRE scenarios in , fossil depletion decreases by 90%, while bulk material requirements increase four-fold compared to baseline levels. In addition, certain wind power and photovoltaics technologies also rely on specialty minerals, such as dysprosium or indium55,56, which are not addressed in the resource depletion assessment method employed here, but are subject to geopolitical supply risks57. The low-carbon transformation, especially if it relies heavily on wind and solar technologies, can be expected to have profound implications for the geopolitical landscape, pointing to the need for flanking the global clean energy effort with an integrated critical materials strategy.
Fossil fuels by far dominate resource surplus costs, the aggregate ReCiPe endpoint indicator for resource depletion (Fig. 6d). This result suggests that the benefit to society stemming from reduced fossil requirements in NewRE outweigh the burden due to additional mineral resource depletion. In addition, it should be kept in mind that much of the resource requirements for wind and solar installations can be attributed to upfront investment for electricity produced later, and that mineral resources are amenable to recycling58, while fossil resources are not.
In terms of technologies, fossil fuels are the major drivers of health impacts and also dominate resource surplus costs; thus, their reduction in the context of climate policies yields substantial benefits (Supplementary Fig. 5). Bioenergy emerges as the greatest driver of ecosystem damage, chiefly due to land occupation and induced loss of natural lands. On the other hand, numerous studies have demonstrated the importance of bioenergy for the 1.5 and 2&#;°C targets3,4,5,18,59, both due to its versatility in substituting fossil fuels and the possibility of generating negative emissions. This underlines the need for an integrated global land management to navigate the tradeoff between climate change mitigation and conservation.
Vitamin C (ascorbic acid) is a required nutrient for a variety of biological functions. Humans and other primates have lost the ability to synthesize ascorbic acid due to a defect in L-gulono-1,4-lactone oxidase, an enzyme that catalyzes the conversion of L-gulonolactone into ascorbic acid. Humans, primates and a few other animals (e.g., guinea pigs) depend on the diet as a source of vitamin C to prevent the vitamin C deficiency disease, scurvy, and to maintain general health. The health-promoting effects of vitamin C can be attributed to its biological functions as a co-factor for a number of enzymes, most notably hydroxylases involved in collagen synthesis, and as a water-soluble antioxidant. Vitamin C can also function as a source of the signaling molecule, hydrogen peroxide, and as a Michael donor to form covalent adducts with endogenous electrophiles in plants. These functions and the underlying mechanisms will be illustrated here with examples from the recent literature. This review focuses on chronic diseases and is not intended to provide an exhaustive account of the biological and clinical effects. Other authors have recently discussed the effects of vitamin C on cancer chemoprevention [1, 2] and in the treatment of cancer [3], sepsis [4], and neurodegenerative diseases [5, 6].
Vitamin C is required for collagen synthesis by acting as a cofactor for α-ketoglutarate-dependent nonheme iron dioxygenases such as prolyl 4-hydroxylase. Investigations into the mechanism of ascorbate-dependent dioxygenases have shown that ascorbate is not consumed in the catalytic cycle in which the co-substrate, α-ketoglutarate, undergoes oxidative decarboxylation to form succinate and a highly reactive iron oxo (FeIV= O) species. The formation of this FeIV= O species is coupled with homolytic cleavage of a C&#;H bond in the substrate molecule, e.g., proline ( ). The reaction cycle reaches completion when the substrate is oxidized and the oxidation state of the enzyme-bound iron changes from +4 to +2 ( ). In the absence of a substrate molecule, the enzyme becomes uncoupled and then ascorbate reduces oxo-iron back to FeII, restoring the enzyme's activity. From competition studies with various inhibitors of prolyl 4-hydroxylase and ascorbate derivatives with modifications in the side chain and in the lactone ring, Majamaa et al. [7] concluded that ascorbate interacts directly with the enzyme-bound iron and acts as &#;an inner-sphere reductant in uncoupled reaction cycles&#;. These authors also concluded that the consumption of ascorbate in a Fenton-like reaction is precluded by the enzyme [7]. The direct interaction between ascorbate and the enzyme-bound iron is similar to Siegel's proposed mechanism of prolyl hydroxylase in which ascorbate coordinates with iron [8, 9]. Structural investigations have established that the iron in human prolyl 4-hydroxylase coordinates with His412, Asp414, and His483 in the catalytic site of the enzyme [10], leaving two coordination sites for binding of the co-substrate, α-ketoglutaric acid, and the last for binding to dioxygen. The cis-oriented oxygen atoms of ascorbate may bind to the enzyme-bound iron similar to α-ketoglutarate [10]. Coordination of ascorbate with enzyme-bound iron would provide the necessary electrons in uncoupled reaction cycles to reactivate the enzyme ( ), consistent with the observation that ascorbate is consumed stoichiometrically in uncoupled reaction cycles [11]. Thus, the role of ascorbate is to keep the nonheme iron in the catalytically active, reduced state.
Scurvy is the prototypical deficiency disease that links insufficient intake of vitamin C to impaired collagen synthesis [12]. Collagen synthesis is required for maintaining normal vascular function but also for tumor angiogenesis. Tumor growth relies on angiogenesis to provide the cancerous tissue with metabolic substrates, growth factors, and oxygen. Low vitamin C levels would therefore be expected to limit tumor growth by compromising collagen synthesis. Telang et al. [13] tested this hypothesis in mice incapable of ascorbic acid synthesis (Gulo&#;/&#; mice with a deletion of the L-gulono-γ-lactone oxidase gene) by measuring the effect of vitamin C supplementation on growth of implanted Lewis lung carcinoma cells. They found that Gulo&#;/&#; mice with low plasma vitamin C levels (< 5 μM) developed smaller tumors when the animals consumed a vitamin C-depleted diet compared to partially or fully vitamin C-supplemented animals. The tumors from the scorbutic animals showed multiple areas of hemorrhage, poorly formed blood vessels, and decreased collagen synthesis [13]. The authors suggest that patients with existing cancer may not benefit from vitamin C supplementation; however, vitamin C deficiency is not likely to be beneficial for human cancer patients.
Arterial Tortuosity Syndrome (ATS) is associated with abnormal collagen and elastin synthesis. Twisting and lengthening of major arteries, as well as hypermobility of the joints and laxity for the skin, are characteristics of this rare and heritable disease, which is caused by defects in the gene SLCA10 that codes for GLUT-10 [14]. Since GLUT-10 is localized in the rough endoplasmic reticulum (ER) [15] where proline and lysine hydroxylation take place and where collagen is prepared for secretion by the Golgi apparatus, Segade [15] hypothesized that the defective GLUT-10 in ATS leads to a decrease in uptake of dehydroascorbic acid by the ER, inadequate availability of ascorbic acid for prolyl and lysyl hydroxylases inside the ER, and to synthesis and extracellular deposition of abnormal collagen and elastin. Segade [15] further hypothesized that a major source of ascorbic acid in the ER is dehydroascorbic acid that is taken up by GLUT-10 in the ER membrane and reduced by protein disulfide isomerase in the lumen of the ER [16]. The dependence of ascorbate availability in the ER on GLUT-10 activity and its relevance to ATS remains to be demonstrated.
It is estimated that a third of preterm births are due to premature rupture of the fetal membranes [17]. Mercer et al. [18] tested the hypothesis that fetal membrane strength can be improved by vitamin C and E supplementation to increase collagen synthesis and to inhibit ROS-induced fetal membrane weakening. In a placebo-controlled study, 13 women with a singleton pregnancy received a combination of vitamin C ( mg/day) and vitamin E (400 IU/day) from the second trimester until delivery. Vitamin supplementation had no effect on rupture strength, did not affect the normal fetal membrane remodeling process that leads to weakening and rupture at term, and did not alter protein levels or activity of matrix metalloproteinase-9 (MMP-9), a marker of fetal membrane remodeling [19]. Collagen content of the fetal membranes was not measured in this study. Thus, supplementation did not have any obvious benefits.
Vitamin C-dependent proline hydroxylation also plays a role in gene transcription mediated by hypoxia-inducible factor (HIF)-1 [20, 21]. Direct transcriptional targets of HIF-1 include genes that regulate growth and apoptosis, cell migration, energy metabolism, angiogenesis, vasomotor regulation, matrix and barrier functions, and transport of metal ions and glucose [21]. Binding of HIF-1 to DNA requires dimerization of α and β subunits. Under normoxic conditions, the HIF-1α subunit is targeted for degradation by HIF-specific prolyl hydroxylases that hydroxylate HIF-1α at proline residues 402 and 564 [22]. Prolyl hydroxylase domain (PHD)2 is the predominant form that regulates HIF activity in vivo [23]. Proline hydroxylation promotes HIF-1α binding to the von Hippel-Lindau tumor suppressor and its ubiquitin-dependent degradation [22], thereby repressing transcription of target genes. Under hypoxic conditions, such as exist in fast growing tumors, HIF-1α hydroxylation is repressed with the result that HIF-dependent gene transcription increases, thus promoting angiogenesis and tumor growth. Because HIF-1α prolyl hydroxylase is stimulated by ascorbic acid [24], low vitamin C levels would reduce HIF-1α hydroxylation and thus stabilize HIF-1α, thereby promoting HIF-dependent gene transcription and tumor growth. Kuiper et al. [25] investigated the impact of ascorbate levels in endometrial tumors, obtained from women undergoing hysterectomy, on HIF-1 activity and tumor pathology. They found lower ascorbate and increased HIF-1α protein levels in more aggressive tumor tissue (endometrioid adenocarcinoma) compared to less aggressive tumor tissue and normal tissue. A significant inverse correlation was observed between ascorbate levels in tumor tissue and markers of HIF-1 pathway activation such as VEGF, which, for the first time, supports the notion that adequate vitamin C levels inhibit tumor progression in humans through inhibition of the HIF-1 pathway [25].
Under normoxic conditions, HIF-1 can be induced by transition metal ions such as CoII, NiII and CrVI [26, 27]. The mechanism by with CoII and NiII activate the HIF-1 pathway is due to cellular depletion of ascorbate by metal-ion catalyzed air oxidation. It has also been suggested that NiII can inactivate prolyl hydroxylase by substitution of enzyme-bound FeII. CrVI showed a transient effect on HIF-1α stability and HIF-1 activity in cultured lung epithelial (1HAEo and A549) cells, which Kaczmarek et al. [27] attributed to ascorbate-mediated conversion of CrVI into inactive CrIII, allowing recovery of cellular ascorbate and restoration of HIF prolyl hydroxylase activity. These authors emphasized the importance of ascorbate levels in the lung to protect against toxicity of metal ions through activation of the HIF pathway.
A potent inducer of HIF-1 activity in vascular smooth muscle cells is angiotensin II, which was shown by Pagé et al. [28] to inhibit hydroxylation of proline 402 in HIF-1α. The mechanism was determined to be angiotensin II-mediated generation of hydrogen peroxide (H2O2) and depletion of cellular ascorbate. Alternatively or additionally, H2O2 and other ROS may also interfere with HIF prolyl hydroxylase by decreasing FeII in the catalytic site [29].
Ascorbic acid has long been recognized as a key player in the ability of neutrophils to kill bacteria. In the presence of bacteria, ascorbate levels in neutrophils increase by up to 30-fold due to uptake of dehydroascorbic acid [30]. The accumulation of ascorbate in neutrophils is thought to protect these cells against damage by ROS that they produce [30]. As NADPH oxidase is the predominant source of ROS in neutrophils, it is conceivable that the protective effect of ascorbate is in part due to prevention of protein damage from reaction with ROS/lipid-derived 2-alkenals [31, 32]. In addition, ascorbate augments NO-mediated generation of ROS in polymorphonuclear leukocytes [33] and prolongs neutrophil NOS expression, NOS catalysis, and oxidative burst [34]. A moderate increase in NO itself leads to a decrease in HIF-1α accumulation [35, 36]. Neutrophil apoptosis and clearance, a normal physiological process in the resolution of inflammation, appears to be regulated by ascorbate through suppression of the HIF pathway [37]. The positive effects of vitamin C on neutrophil function and clearance could provide a rationale for vitamin C supplementation in individuals with low vitamin C status, e.g. in hospitalized, elderly patients who are at enhanced risk for being infected with bacteria.
Pre-eclampsia is a complication that develops in about 5% of pregnant women during the second half of gestation. The syndrome is characterized by hypertension and proteinuria. Reduced placental perfusion has been identified as a causal factor and has been associated with endothelial activation [38]. Several authors have hypothesized that oxidative stress and lipid peroxidation (LPO) play an important role in the development of pre-eclampsia [39, 40]. A recent systematic review and meta-analysis conducted by Gupta et al. [41] revealed increased levels of serum malondialdehyde, increased total serum thiobarbituric acid-reactive substances (TBARS), marginally decreased erythrocyte superoxide dismutase (SOD), and decreased serum vitamin C and E levels in pre-eclampsia cases compared to controls. The authors concluded that pre-eclampsia is associated with increased oxidative stress and decreased antioxidant vitamin levels [41]. Such findings have provided the rationale for a number of antioxidant trials aimed at reducing the rate and severity of pre-eclampsia. Supplementation with vitamin C and E proved a beneficial effect on the rate of pre-eclampsia in a randomized, placebo controlled trial with 283 women at risk [42]. Subsequent larger trials showed no beneficial effects of vitamin C and E supplementation on the rate of pre-eclampsia [43-49].
McCance et al. [50] studied the effect of vitamin C ( mg/day) and E (400 IU/day) supplementation in 379 pregnant women with type 1 diabetes, who were at higher risk for developing pre-eclampsia, presumably due to increased oxidative stress (DAPIT trial). These authors found no effect of vitamins C and E on the primary endpoint, pre-eclampsia, compared to 382 placebo-treated women (p = 0.20). However, the supplemented women had fewer preterm births (< 37 weeks, p = 0.046). In subgroup analysis, vitamin supplementation showed an effect on pre-eclampsia in two of 11 women with low antioxidant status at baseline. The authors concluded that vitamin supplementation may be beneficial in pregnant women with low antioxidant status. According to the authors, negative outcomes in previous vitamins C and E supplementation trials may be attributed to adequate vitamin C and E status of the women at baseline [50]. As pointed out by Talaulikar [51], the DAPIT supplementation study did not include measures of oxidative stress in order to determine whether the administered vitamin doses were effective in reducing oxidative stress.
A multi-center, randomized, double-masked, placebo-controlled vitamin C ( mg) and vitamin E (400 IU) supplementation trial conducted in the U.S. with 9,968 low-risk nulliparous women showed no effect in the prevention of spontaneous preterm birth at less than 37 and 35 weeks of gestation [52]. Preterm births due to premature rupture of membranes were less frequent before 32 weeks of gestation (0.3% vs. 0.6% adjusted OR 0.3-0.9) [52]. A Canadian study of the effects of vitamin C ( mg) plus E supplementation study (400 IU) with 2,363 women failed to reduce the rate of pre-eclampsia or gestational hypertension, but did increase the risk of fetal loss or perinatal death and premature rupture of membranes (INTAPP trial, [49]). A similar study conducted by Villar et al. [44] showed no effect of vitamin C ( mg/day) and E (400 IU/day) supplementation on pre-eclampsia, eclampsia, low birthweight, and perinatal death in at-risk pregnant women with low nutritional status from India, Peru, South Africa, and Vietnam (WHO trial). In this latter study, any effect of vitamin supplementation in women with low vitamin status may have remained undetected due to lack of measurements of vitamin levels and poor compliance [44]. Another study conducted in India with 140 normotensive pregnant women, however, revealed that preterm births were associated with oxidative stress, measured as malondialdehyde in maternal and in cord blood (p < 0.05), and with elevated vitamin C concentrations (p < 0.05) compared to at-term births [53].
Taken together, the majority of studies has failed to support the earlier stated hypothesis that pre-eclampsia and preterm births can be prevented by vitamin C or by combined vitamin C and E supplementation, despite the well-documented relationship between pre-eclampsia / preterm birth and oxidative stress. A mechanistic study into the effects of vitamins C and E on trophoblast apoptosis and authophagy, a common feature in placentas from pregnancies complicated by pre-eclampsia that results in impaired circulation, was conducted by Hung et al. [54] to shed light on the clinical findings. Using cultured trophoblasts and villous explants obtained from human term placentas, the authors observed reduced apoptosis and autophagy in trophoblasts exposed to 50 μM vitamin C and 50 μM vitamin E under normoxic conditions for 48 h. By contrast, they observed enhanced apoptosis and autophagy when the vitamin-supplemented cells were subjected to two cycles of hypoxia (8 h) and reoxygenation (16 h). The authors concluded that concomitant administration of vitamins C and E has differential effects on apoptosis and autophagy in placental cells under normoxia compared to hypoxia-reoxygenation, which may explain the adverse effects of vitamin C supplementation on placental function found in some of the clinical studies. Another explanation for the results from inconclusive supplementation trials was provided by Talaulikar and Manyonda [55] who argued in a reaction to the INTAPP publication (ref. [49]) that oxidative stress is unlikely to be the cause of defective trophoblast invasion which plays a key role in the pathophysiology of pre-eclampsia.
Scurvy is rare in the general population but is still prevalent today in populations at risk. In addition to poor diet, alcoholism [56], elderly age, socioeconomic deprivation [57], mental illness [58], malabsorption disorders, kidney failure, hemodialysis [59], and peritoneal dialysis [60] have been identified as risk factors for low vitamin C status and developing clinical symptoms of scurvy [61-63]. In a geriatric hospital in Paris, France, 18 elderly patients (12%), who showed clinical symptoms of scurvy, had low serum levels of ascorbic acid compared to control patients (6.2 ± 6.0 μM versus 28 ± 24 μM, p < 0.001) [64]. These data suggest that vitamin C status should be checked routinely in elderly patients admitted to geriatric institutions.
Plasma vitamin C levels can decrease rapidly as a result of acute inflammation produced by sepsis [4], myocardial infarction, cancer, medication, surgery [65] or use of a cardiopulmonary bypass machine [66]. Alexandrescu et al. [67] described a case of a 50 year old man who was treated for metastatic renal-cell carcinoma with high-dose interleukin-2 (IL-2), an inflammatory cytokine, and consequently developed acute symptoms of scurvy: petechiae and perifollicular hemorrhage on the arms and legs, and gingival bleeding. The patient's serum vitamin C decreased from 17 μM to 6 μM following treatment with IL-2, demonstrating that &#;symptoms of scurvy occur acutely whenever a state of chronic depletion of vitamin C reaches a critical threshold [67]&#;. The patient recovered from the clinical symptoms of acute scurvy after seven days of discontinuation of IL-2 treatment. The effect of IL-2 treatment on vitamin C status was earlier described by Marcus et al. [68, 69].
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