Eco-Environment & Health 2 (2023) 246–251 Contents lists available at ScienceDirect Eco-Environment & Health journal homepage: www.journals.elsevier.com/eco-environment-and-health Perspective Human-driven global nutrient imbalances increase risks to health Josep Penuelas a, b, *, Jordi Sardans a, b a CSIC, Global Ecology Unit CREAF-CSIC-UAB, 08193 Bellaterra, Barcelona, Catalonia, Spain b CREAF, 08193 Cerdanyola del Valles, Barcelona, Catalonia, Spain A R T I C L E I N F O A B S T R A C T Keywords: Human-induced inputs of nitrogen (N) and phosphorus (P) into the biosphere have reached unprecedented levels, Nitrogen particularly N, leading to an escalating global anthropogenic N:P ratio. This ratio has emerged as a significant Phosphorus driver of environmental change, impacting organisms, ecosystems, and global food security. However, the im- N:P ratio plications of this ratio for human health have been largely overlooked and remain uncertain. This article aims to Non-infectious diseases Infectious diseases fill this knowledge gap by exploring the potential effects of N:P ratios on both non-infectious and infectious Medical treatments diseases. Preliminary data emphasize the importance of investigating the influence of N:P ratios on human health, suggesting a potential role in the rise of non-infectious diseases, such as cancer, as well as the proliferation of infectious diseases, including Zika and malaria. These findings highlight the urgent need for increased attention from the scientific community and policymakers regarding the complex impacts of the human-induced biospheric N:P ratio. It is crucial to investigate and understand the underlying mechanisms and drivers behind these effects. Furthermore, there is significant potential for improving human health through the manipulation of N:P ratios and the availability of N and P. This applies not only to medical treatments but also to innovative fertilizer management strategies. These avenues present promising opportunities to address the challenges associated with human health in an ever-changing world. 1. Human impacts on nitrogen and phosphorus cycles approximately 30 on a molar basis for anthropogenic inputs, while values for principal ecosystem components range from 16 (ocean water, plankton) In recent decades, human activities have had a profound impact on to 22 (soils). However, at local-regional scales, the imbalance in N and P the nitrogen (N) and phosphorus (P) cycles, leading to unprecedented inputs may be even greater due to uneven distribution and differences in releases of N into the environment and resulting in a nutrient imbalance environmental mobility. P tends to have low water solubility and volatili- between N and P in the biosphere [1]. Anthropogenic inputs of reactive N zation, often adsorbing and precipitating in the soil as salt minerals or being to the biosphere, driven by fossil fuel combustion and fertilizer use, have buried in sediments near emission sources. In contrast, N is more water- increased significantly, contributing to annual N releases of 25–33 Tg N soluble and volatile, spreading over larger distances from its sources [4]. and >150 Tg N, respectively. Additionally, leguminous crops and rice fix P enrichment is common in agricultural soils, as it has low solubility approximately 90 Tg N per year from atmospheric N2. Some regions have and a tendency to precipitate and become immobilized. This has led to also experienced N eutrophication [2]. On the other hand, anthropogenic declines in N:P ratios in several parts of the world [4,5], particularly in releases of P have remained relatively stable and lower compared to N, regions with high livestock density where manure waste exhibits very primarily originating from fertilizer use (22–26 Tg P per year) and animal low N:P ratios [6]. While most continental and coastal areas have expe- feed. However, these human-induced P fluxes, although comparable to rienced increased N:P ratios due to N spreading capacity, cropland soils natural global fluxes [3], have been shown to cause regional soil and and adjacent habitats receiving untreated or diffuse wastes and leachates water eutrophication, influencing the global biogeological P cycle. have witnessed decreased N:P ratios. The difference in the anthropogenic release of reactive N and P has led The N:P ratio plays a crucial role in determining community structure to an overall increase in the global mean N:P ratio, which now stands at and function, especially when concentrations of both N and P are not * Corresponding author. E-mail address: Josep.penuelas@uab.cat (J. Penuelas). https://doi.org/10.1016/j.eehl.2023.08.003 Received 2 July 2023; Received in revised form 6 August 2023; Accepted 12 August 2023 Available online 24 August 2023 2772-9850/© 2023 The Author(s). Published by Elsevier B.V. on behalf of Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment (MEE) & Nanjing University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). J. Penuelas, J. Sardans Eco-Environment & Health 2 (2023) 246–251 limiting. Plankton’s protein synthesis rate, for instance, is dependent on economically advanced countries has led to food overproduction, while the amount of P-rich RNA produced, leading to a negative correlation low levels of fertilizer use in economically developing countries have between cellular N/P ratio and protein synthesis rate, resulting in faster helped prevent malnutrition [12]. These disparities in fertilizer use have growth rates of plankton with lower N/P ratios [7]. This negative cor- contributed to variations in human growth and development. Notably, relation has ecological consequences for the structure and functioning of variations in per capita intake of N and P, as well as the associated bal- ecosystems, as observed in various ecosystem types [4]. ance in the N:P ratio, correlate with differences in the average height of In addition to N and P imbalances, human activities have also men born in high-income countries. This correlation is even more sig- caused imbalances among other elements, such as carbon (C), N, iron, nificant than socioeconomic or sanitary variables such as GDP, the zinc, calcium, and potassium, in plant tissues [8,9]. Increasing atmo- human development index, and birth weight, as indicated by integrated spheric CO2 concentrations are likely drivers of increased C concen- analyses of data from FAO (2006), OECD (2022), and WHO [10]. trations in plants, consequently reducing the concentrations of these other elements [8,9]. 2.2. Non-infectious diseases While the environmental impact of human-driven N and P inputs on managed and semi-natural ecosystems and food security is well- 2.2.1. Nitrogen immunological and oncological effects documented [1–4], their direct effects on human health are less under- The positive effects of increased N and P intake on human growth and stood. This article aims to review current research on the potential im- development are accompanied by potential risks to the triggers of non- pacts of N:P ratios on human health (Fig. 1), shedding light on this infectious diseases. For instance, the global annual N fertilization of important yet understudied aspect. wheat has significantly increased from 9.8 to 93.8 kg/ha between 1961 and 2010 [13], reflecting the overall rise in N fertilizers across different 2. Impact of nutrient imbalances on human health types of farmland (11.3–107.6 Tg) [14]. This escalation in N fertilization has raised concerns about the potential increase in the risk of health 2.1. Growth disorders, including coeliac disease, due to the elevated content of allergenic proteins [15], such as gluten [16,17], particularly the gliadin Humans, like other species, are profoundly influenced by elemental fraction [18–20], which is known to trigger and sustain this disease and stoichiometric changes in their environment. The impact of [21–23]. Notably, a higher availability of N has been associated with anthropogenic shifts in the input of N and P into the biosphere, and the increased expression of gliadin genes [20]. resulting changes in N:P ratios, have cascading effects on the human food Anthropogenic increases in N, particularly in its active/reactive forms chain [10,11]. In the past, the excessive use of N fertilizer in such as nitrate (NO3 ) and ammonium, and exposure to atmospheric Fig. 1. Schematic diagram of the impact of N:P on human food security and health. 247 J. Penuelas, J. Sardans Eco-Environment & Health 2 (2023) 246–251 nitrogen dioxide in occupational and domestic settings, can have adverse with prostate cancer in epidemiological studies of American male phy- effects on human health. However, the pervasive presence of environ- sicians and Swedish males [52]. In Swedish women, cancer (all types) mental pollutants derived from reactive N complicates the interdisci- mortality increased by 44% (hazard ratio 1.44; 95% confidence interval plinary assessment of their harmful effects on human health [24]. 1.23–1.69) when consuming three glasses of milk per day compared to The increasing concentrations of nitrates in groundwater resulting one glass [53]. In a clinical study of 9,686 adults aged 20–80, with an- from surface leaching of fertilizers, as well as industrial, animal, and alyses adjusted for demographics, cardiovascular risk factors, kidney human waste, pose health risks when consumed in drinking water, function, and energy intake, higher phosphorus intake was associated especially for children under five years old [25]. For example, the with higher all-cause mortality in individuals, with this association being leaching of livestock waste from cropland has led to high levels of water particularly significant among individuals with a daily phosphorus intake pollution in aquifers in Europe, China, India, Reunion Island, and various exceeding 1,400 mg/d [54]. regions of the USA, Canada, and Australia [26–33]. Nitrates and nitrites These findings emphasize the complex relationship between phos- are also used in processed meats as additives in meat curing [34] and their phate levels, dietary intake, and cancer incidence. Tumour cells exhibit intake has been related to breast and prostate cancer risk in humans [35]. altered phosphate accumulation and metabolism, which can contribute to their growth and proliferation. Furthermore, the accumulation of 2.2.2. Phosphate and cancer phosphorus in certain cropland soils and its subsequent uptake by crops High dietary consumption of phosphate (PO4) has been found to raise concerns about elevated phosphorus concentrations in food. How- stimulate the growth of lung and skin tumours in experimental animals, ever, the direct implications of these changes on human health are still potentially due to increased growth-promoting cell signaling, neo- not fully understood. vascularization, and chromosome instability in the presence of excessive Further research is needed to explore the specific mechanisms phosphate [36]. underlying the association between phosphate levels and cancer Tumour cells are known to exhibit higher expression levels of phos- development. Additionally, investigating the global-scale link between phate cotransporters and accumulate larger quantities of inorganic phos- phosphorus accumulation in crop soils, phosphorus concentrations in phate compared to healthy cells [36,37]. For example, lung and colon food, and their impact on human health is crucial. Understanding the tumours have been found to contain approximately double the amount of P effects of excessive dietary phosphorus intake and the use of phos- and RNA concentration compared to healthy tissue, resulting in lower N:P phorus additives in food production will help to elucidate potential ratios [38,39]. Elser et al. [38-40] analyzed the elemental composition of health risks and guide strategies for maintaining a balanced and normal and tumour tissues from the lung, colon, liver, and kidney. healthy diet. Consistent with the Growth Rate Hypothesis (GRH), they observed that In conclusion, medical studies have underscored the role of phos- lung and colon tumours exhibited significantly higher P and RNA con- phate toxicity as a pathophysiological determinant in cancer cell growth, centrations (as a fraction of dry weight) and lower N:P ratios compared to with tumour cells exhibiting higher expression levels of phosphate their respective normal tissue. However, they did not find significant dif- cotransporters and storing larger amounts of inorganic phosphate ferences in %P and %RNA between malignant and normal tissues in the compared to normal cells. Disruption of phosphate homeostasis has been liver and kidney tumour tissues. Moreover, the P present in RNA accounted associated with the development of various human tumours [36]. for a significantly larger fraction of the total biomass P in malignant tissues than in normal tissues. These findings support the GRH, which suggests 2.2.3. Therapies for cancer that under conditions where neither N nor P is limiting, a low N:P ratio is Chemotherapy typically results in a significant reduction in tumour associated with a high growth rate, as P-rich RNA becomes the limiting populations, often by a factor of a thousand, before resistance emerges. factor for synthesizing amino acids and building proteins. However, complete eradication of the tumour population is essential to Considering the growing evidence linking phosphate and N:P ratios to prevent tumour recurrence, as the extracellular conditions following certain cancer incidences in humans, it is crucial to consider the human- chemotherapy can stimulate the proliferation of surviving tumour cells driven impacts on global P and N cycles [3,41] and their potential con- due to the release of substantial amounts of phosphate and other cellular sequences on P concentrations and N:P ratios in food. Accumulation of P material upon tumour cell death [55]. Therefore, integrating stoichio- in some cropland soils has been reported, leading to increased P uptake metric theory into cancer treatment strategies may enhance the efficacy by crops and potentially influencing food composition by elevating P of chemotherapy. For example, post-chemotherapy dialysis, which concentrations [42–44]. Although studies have shown high levels of P selectively removes circulating phosphate from the blood plasma, could uptake in both crops and non-crop plants under conditions of high soil P be considered to minimize the proliferation of surviving tumour cells and concentrations, the global-scale link between P accumulation in crop facilitate improved immune system management [40]. soils, P concentrations in food, and the resulting implications for human However, it is not only phosphate itself that plays a critical role; the N:P health remains unknown. Further research is needed to explore the ef- ratios may also be crucial in enhancing the effectiveness of cancer thera- fects of increased dietary P intake, as excessive P intake has been pies. One promising approach in combating cancer growth involves tar- inconsistently linked to health problems such as bone health, cancer risk, geting the p53 tumour suppressor gene. The successful application of this and heart failure associated with the augmented use of P additives in therapy relies on the specific delivery of the p53 gene to cancer cells. The foods [45–47]. protein carriers involved in the process possess structures—such as Several reports have highlighted the links between cancer incidence morphology, size, and surface charges—that are highly influenced by the and phosphate levels in the human body. Chromosome instability, a N:P ratio (the ratio of nitrogen to phosphate groups). It has been observed characteristic of cancer cells, has been positively associated with high that the N:P ratio significantly impacts the efficiency of gene transfection, a phosphate concentrations. For example, hyperphosphatemia has been process that involves introducing nucleic acids into eukaryotic cells using shown to increase the risk of chromosome aberrations in the parathyroid nonviral methods. Thus, the N:P ratio can be precisely adjusted to achieve glands of patients with hyperparathyroidism [48], and high levels of desired levels of protein expression and apoptosis. The notable advantage dietary phosphate have been linked to increases in lymphocyte geno- of this proposed system lies in the use of N:P ratios as a customizable toxicity [49]. A 24-year monitoring study as part of the Health Pro- parameter that not only modulates vector properties but also controls the fessionals Follow-Up Study revealed that high levels of dietary phosphate extent of plasmid DNA delivery, protein production, and, consequently, the are independently associated with lethal and high-grade prostate cancer efficacy of p53-mediated cancer therapy [56,57]. Therefore, manipulating [50]. Milk and dairy products contribute the highest percentage of N:P ratios through dietary interventions or other strategies represents an phosphate intake in the American diet [51]. Newmark and Heaney additional tool that warrants investigation in the fight against certain types proposed that phosphate from dairy products is a risk factor correlated of human non-infectious diseases. 248 J. Penuelas, J. Sardans Eco-Environment & Health 2 (2023) 246–251 2.3. Infectious diseases composition of the mosquito community, including species with varying degrees of vectoring efficiency. Studies conducted in subtropical, There is emerging evidence that gaining a better understanding of the P-limited oligotrophic wetlands have demonstrated mechanistic links role of environmental stoichiometry in the structure, organization, and between nutrient enrichment, wetland vegetation, and vector produc- function of human microbial communities can contribute to the man- tion. In these wetlands, P-enriched runoff from agricultural land and agement and control of disease vectors. Analysis of stoichioproteomics in human settlements has resulted in the replacement of sparse macro- different body-site locations has revealed variations in the N content of phytes (rush) by tall, dense species (cattails), impacting the larval mos- microbial proteins, with skin and nasal proteins, for example, being quito community [65,66]. Similarly, increased N:P ratios in a western particularly nitrogen-rich. These varying proportions of bio-elements in Mediterranean river basin, attributed to improved wastewater treatment, proteins from distinct organ tissues are likely linked to the local envi- have led to higher macrophyte density, and consequently to increased ronments at different human body sites, including atmospheric exposure abundance, and expansion of populations of the black fly (Simulium and food intake rates [58]. Moreover, as atmospheric carbon dioxide erythrocephalum), a vector of several pathogenic microbes [67,68]. levels increase globally due to the burning of fossil fuels, human plant Overlap in parasite-host stoichiometric requirements has been food sources show increased C:N and C:P ratios [59,60], suggesting that observed, particularly in the case of N:P ratios in a freshwater cyano- humans are altering the elemental stoichiometry that we provide to our bacterium host (Planktothrix rubescens), which were positively correlated symbiotic gut bacteria. This can have impacts on the species structure of with experimental N:P ratios. These host responses were mirrored in the gut microflora, which requires further analysis. N:P stoichiometry and the production of toxic microcystins by the fungal Nutrient stoichiometry, such as N:P ratios, may influence traits, parasite Rhizophydium megarrhizum (Chytridiomycetes), while zoospore growth, and the geographical distribution of human parasites, thereby size exhibited a negative association with N:P ratios [69]. Consequently, impacting the incidence and severity of vector-borne diseases. Paseka and fungal parasites demonstrate a trade-off between zoospore size and Grunberg [61] examined 27 macroparasite taxa from four phyla that infect production. As zooplankton graze on chytrid zoospores, changes in vertebrate and invertebrate hosts in freshwater ecosystems in New Jersey. parasite production, stoichiometry, and zoospore cell size can have im- They observed that the allometric scaling of phosphorus across species plications for aquatic food web dynamics. supports the GRH, which predicts that smaller taxa require more phos- The GRH provides evidence of how parasite–host relationships are phorus to support their relatively higher growth rates. Across all species, influenced by N:P ratios, as the growth rates of hosts with low C:P-ratio parasite phosphorus concentrations scaled negatively with body size, while diets are positively associated with levels of viral infections [70] and C:P ratios scaled positively. Similar relationships between parasite phos- bacterial infections [71]. Although the understanding of this relationship phorus concentrations and body size were observed at the phylum level in human pathogenic parasites is limited [72], this association could be and within individual species. Nitrogen concentrations and C:N ratios were of concern for human health in countries where diets are high in P [73]. related to the life-cycle stage, with non-reproductive parasite stages having For example, N:P ratios drive the growth of non-pathogenic bacteria and lower nitrogen concentrations and higher C:N ratios than actively repro- associated blooms in aquatic systems [7,11], suggesting that shifts in N:P ducing parasites. Organismal stoichiometry was found to be linked to ratios might also influence the growth and proliferation of pathogenic ecological function, and the wide variation in macroparasite stoichiometry bacteria, such as Vibrio cholerae, the causative agent of cholera, and likely generates diverse patterns in host-parasite nutrient dynamics, as well heterotrophic bacteria in aquatic environments [72]. as variable relationships between parasitism and nutrient cycling. This Effects of shifts in environmental stoichiometry on the incidence of suggests how the N:P availability ratio in the environment (water and soil) vector-borne parasitic diseases in humans may be influenced by their can affect parasites and, consequently, the performance of several human impacts on hosts [74]. This is evident from the effects of aquatic infectious diseases. ecosystem stoichiometry on the distribution and population dynamics of Aalto et al. [62] reviewed shifts in host-parasite interactions under changing nutrient ratios and observed that the outcome of infection may depend on the overlap in the stoichiometric requirements of the host and the parasite. The authors further hypothesized that environmental nutrient enrichment alters infectivity dynamics, leading to fluctuating selection dynamics in host-parasite coevolution. Shifts in parasite stoichiometry that result in changes in ecosystem function [61] are likely to drive patterns in host-parasite nutrient dynamics, including nutrient cycling, as well as the transmission and prevalence of vectored diseases. These dynamics may depend on overlaps in stoichiometric requirements between hosts and parasites and could potentially impact host-parasite coevolutionary pro- cesses [62]. In a long-term chemostat experiment conducted by Larsen et al. [63], the marine cyanobacterium Synechococcus was challenged with a lytic phage while manipulating nutrient stoichiometry. The researchers observed alterations in the stability of host-parasite interactions and the underlying mode of coevolution. Nutrient stoichiometry can affect eco-evolutionary feedbacks in ways that may alter the dynamics and functioning of environmental and host-associated microbial communities. Shifts in environmental N:P ratios are likely to impact globally important human diseases, such as mosquito-vectored malaria, which annually causes an estimated 2 million deaths, with particularly severe effects on children under the age of five [64]. Ecosystem processes operating on various spatio-temporal scales drive the diversity and abundance of aquatic mosquito larvae that may carry malaria-causing protist parasites (Plasmodium spp.). For instance, shifts in nutrient stoi- chiometry can affect aquatic plant communities, which provide protec- tion from mosquito predators and serve as substrate for bacteria Fig. 2. 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