Could environmental exposure and climate change Be a key factor in the rising incidence of early onset colorectal cancer?

Abstract

The emergence of early onset colorectal cancer (EOCRC) is believed to result from the complex interplay between external environmental factors and internal molecular processes. This review investigates the potential association between environmental exposure to chemicals and climate change and the increased incidence of EOCRC, focusing on their effects on gut microbiota (GM) dynamics. The manuscript explores the birth cohort effect, suggesting that individuals born after 1950 may be at higher risk of developing EOCRC due to cumulative environmental exposures. Furthermore, we also reviewed the impact of environmental pollution, including particulate matter and endocrine disrupting chemicals (EDCs), as well as global warming, on GM disturbance. Environmental exposures have the potential to disrupt GM composition and diversity, leading to dysbiosis, chronic inflammation, and oxidative stress, which are known risk factors associated with EOCRC. Particulate matter can enter the gastrointestinal tract, modifying GM composition and promoting the proliferation of pathogenic bacteria while diminishing beneficial bacteria. Similarly, EDCs, can induce GM alterations and inflammation, further increasing the risk of EOCRC. Additionally, global warming can influence GM through shifts in gut environmental conditions, affecting the host's immune response and potentially increasing EOCRC risk. To summarize, environmental exposure to chemicals and climate change since 1950 has been implicated as contributing factors to the rising incidence of EOCRC. Disruptions in gut microbiota homeostasis play a crucial role in mediating these associations. Consequently, there is a pressing need for enhanced environmental policies aimed at minimizing exposure to pollutants, safeguarding public health, and mitigating the burden of EOCRC.

1. Introduction

Disease phenotype emerges from a complex interaction between genetic predisposition and environmental factors. While genetic research has made substantial leaps since the invention of whole gene and exome sequencing, understanding the environmental influence on diseases remains vague area that requires further exploration. The concept of “Exposome” introduced in 2005 seeks to study the non-genetic factors of diseases [1], analyzing how cumulative environmental exposures, from internal factors like metabolism to external influences such as toxins and societal pressures, contribute to disease risk and progression [2]. It involves temporally measuring all of the exposures that individuals accrue over their lifetime [3]. These exposures can either act directly on the human biological processes including hormone production and function, inflammation, DNA damage, and gene suppression or overexpression [4] or have indirect effects manifested through lifestyle choices related to indoor living, obesity, and stress [5,6]. Current initiatives like the Human Exposome Project and the Human Early-Life Exposome)HELIX(project aim to decode the relationship between exposomes and disease onset [7]. Despite these efforts, the intricate mechanisms that link environmental exposures, climate change, and their subsequent impact on individuals’ health is not yet fully understood.

Colorectal cancer (CRC) is one of the most preventable malignancies, with its development closely linked to a dynamic interplay between internal factors and external exposures affecting the gut microbiota (GM). The rising incidence of CRC worldwide especially among the young age group is drawing attention to the pivotal role of environmental exposures in disease etiology. In fact, current available data suggest that the increasing EOCRC incidence is most likely due to external factors on the human body, rather than shifts in the human genome. This review focuses on exploring the potential mechanisms by which potentially linking environmental contaminants and climate change to shifts in GM composition. We aim to understand how these changes may influence the early onset of colorectal cancer (EOCRC), contributing to its initiation and progression. The work stresses the urgency for a deeper understanding of the environmental dimensions of CRC, highlighting the need for strategies that address these external factors as part of comprehensive cancer control.

2. Early onset colorectal cancer (CRC)

2.1. Incidence and risk factors for EOCRC

Colorectal cancer (CRC) is the third most common form of cancer globally, with almost 2 million new cases annually, and it is the second leading cause of cancer-related deaths worldwide [8]. While there has been a significant reduction in CRC incidence among individuals above 50 years old, there is a concerning increase in EOCRC among those below 50 years old. The incidence of EOCRC is predicted to rise by over 140 % by 2030 [9,10]. It is believed that both internal and external factors contribute to the initiation and progression of these cancers, and reducing the age of screening is currently the only strategy to combat the rising incidence of young-onset cancers [11]. It is not yet understood why there has been such an increase in EOCRC. Despite extensive gene characterization and identification of thousands of mutations associated with cancer, only a limited number of molecular pathways responsible for driving carcinogenesis have been identified, and the mechanisms behind many genetic signatures remain unknown [12,13]. While genetic or germline mutations may cause 10–15 % of CRC cases, environmental factors have an attributable risk of 80–90 %. CRC is widely recognized as a disease influenced by environmental factors, making the recent surge in EOCRC cases concerning for healthcare professionals and environmental scientists alike. Therefore, it is crucial to consider the interplay between genetic and environmental factors, including gene-environment interactions, when evaluating susceptibility, disease expression, and risk.

2.2. Exposome framework in EOCRC

Environmental exposure refers to biological, chemical, or physical changes that adversely affect health, survival, or other activities of living organisms or that alter the environment in undesirable ways. People can be exposed to pollutants from various sources such as contaminated air, water, food, soil, and health products [14]. To comprehend the impact of environmental exposure on the risk of EOCRC, we have adopted Vermeulen et al.'s exposure framework, which classifies environmental exposure into four categories [15]. Each category consists of a list of factors and chemicals that may directly or indirectly affect human health, as illustrated in Fig. 1. To make the framework specific to EOCRC's proposed mechanisms, we have adjusted it by incorporating the current literature's understanding of colorectal carcinogenesis. Chronic inflammation, epigenetic changes, and GM disturbance [9] are believed to be responsible for the development of EOCRC. As a result, we have modified the Vermeulen framework by including these factors.

Fig. 1.

Exposome framework and “birth cohort effect” in EOCRC (Adapted from Ref. [15] with permission).

The framework depicted in the figure consists of factors that do not possess carcinogenic properties inherently, but they contribute to the creation of conditions that promote the production and exposure to known carcinogens or disruptions in GM. For instance, climate change has led to longer wildfire seasons, resulting in an extended release of air pollutants that can spread over long distances, augmenting the number of individuals affected and the quantity of carcinogens in the air [16,17]. Moreover, some carcinogens released can have a long half-life, such as persistent organic pollutants (POPs), which can accumulate in the food chain and harm humans, despite being withdrawn from the market due to their carcinogenic properties [18]. Originally, there were only twelve compounds, known as the “dirty dozen” primarily consisting of insecticides. These compounds were intended to be prohibited following the implementation of the Stockholm Convention in 2001. However, the list has since expanded to include thirty-two POPs, many of which are unintentionally produced, such as through wildfires. These POPs have diverse effects, including reproductive issues, disruption of the endocrine system, and carcinogenic properties observed in animal testing, as exemplified by perfluorooctane sulfonate or C8. Another instance is polychlorinated biphenyls (PCBs), which were banned in 1977 due to their toxicity but persist in significant quantities within the environment, leading to disturbances in the GM [19].

2.3. Birth cohort effect in EOCRC

Knowing that CRC progresses slowly, with a single event or exposure that occurred many years prior to diagnosis could potentially initiate carcinogenic transformation [20], experts have proposed that EOCRC may be explained by the “Birth Cohort Effect” [[21], [22], [23]]. According to this notion, individuals born during certain time periods are more susceptible to the disease than other generations/groups. It is thought that the frequency of EOCRC has been rising among generations born after 1950. Each subsequent generation since then faces a higher risk of developing EOCRC [24]. This heightened risk can be caused by the accumulation of both internal and external factors throughout a person's life that progressively increase their risk of developing cancer over time [24]. Early life factors such as delivery mode, nutritional intake, antibiotics use, childhood, and early adulthood exposures, diet, smoking, chronic health conditions, and environmental exposures may contribute to this trend [9,[25], [26], [27], [28], [29]]. To develop effective preventive measures and early interventions for cancer, it is crucial to understand how these different risk factors and exposures interact with each other. Longitudinal studies that track participants over time and collect clinical records, exposure details, and biospecimens are necessary to provide evidence on the disease risk factors and plan preventive measures accordingly.

2.4. Interplay between environment, epigenetics, and microbiota

Environmental exposures are increasingly recognized for their roles in modulating epigenetic mechanisms, which in turn contribute to the pathogenesis of various cancers, including EOCRC. DNA methylation, a key epigenetic modification, typically involves the addition of a methyl group to the cytosine bases within CpG dinucleotides and can lead to changes in gene expression without altering the DNA sequence itself. This methylation process is highly responsive to environmental factors, such as dietary nutrients, toxins, and microbial products from the gut microbiome [30]. Moreover, certain environmental toxins have been shown to disrupt DNA methylation, potentially silencing tumor suppressor genes or activating oncogenes, hence initiating a cascade of carcinogenic events [31].

Furthermore, the intricate crosstalk between the GM and the host's immune system can mediate chronic inflammation, which has been implicated in DNA methylation alterations. Microbial dysbiosis can lead to the production of pro-inflammatory cytokines and other inflammatory mediators that may induce DNA methylation changes, affecting gene expression profiles involved in cell proliferation, apoptosis, and DNA repair mechanisms. This inflammation-driven methylation has been associated with the silencing of genes involved in immune surveillance and tumor suppression, providing a conducive environment for cancer progression [32]. Chronic exposure to inflammatory stimuli from disrupted microbiota composition thus stands as a significant risk factor for carcinogenesis, highlighting the potential of targeted dietary and probiotic interventions to mitigate such risk by restoring a balanced microbial ecosystem [33]. These findings highlight the need for more research into the specific environmental factors and their epigenetic impacts, to inform prevention and treatment strategies for EOCRC.

3. Human GM and EOCRC

The dynamic interaction among various factors is believed to lead to cancer development in the colon by causing DNA damage, epigenetic alterations, or disturbances in the GM. Current research indicates a strong link between modifications in the host's microbiome and the development of EOCRC [34]. In fact, GM is considered a hidden metabolic organ of the human body influencing human health and diseases [35]. The microbiome's profound effect on health and homeostasis necessitates the need to understand how environmental exposures can alter the microbiome and subsequently influence host reactions [36]. The human gastrointestinal tract houses a rich and ever-changing assortment of microorganisms, collectively referred to as the gut microbiome. This ecosystem contains a genomic diversity that exceed that of human genome. In the context of microbiome composition, host genetics are shown to have a relatively minor influence, contributing less than 2 % compared to the influence of environmental factors [37]. This highlights the importance of considering the microbiome in the toxicological risk assessment of environmental substances [38]. Emerging evidences have implicated disturbances in the GM as a major contributor to the development of environmentally induced colorectal cancer at different ages [9,[39], [40], [41], [42], [43], [44], [45], [46], [47]]. Interestingly, some of the GM implicated in cancer development are also present in the intestines of healthy individuals, complicating our understanding of carcinogenic processes and indicating that the context within the host's environment is pivotal.

3.1. Homeostasis of human GM

The human microbiome comprises trillions of bacteria, viruses, and fungi that are crucial in metabolizing various substances, including nutrients, drugs, and toxins [48]. The GM is highly individualized and influenced by both genetic and environmental factors, co-evolving with the host to maintain structural integrity and homeostasis through communication with host cells. The microbiome is involved in a range of physiological functions mainly in maintaining the gut barrier integrity [49], host immunity [50], and pathogen metabolism [51]. The metabolism of ingested materials produces a wide range of biologically active compounds that can act as hormones, neurotransmitters, or other signaling molecules that influence host metabolism, behavior, and disease susceptibility [52,53]. For instance, the fermentation of complex carbohydrates in the gut generates short-chain fatty acids (SCFAs) that modulate the immune response, decrease inflammation, and help maintain intestinal barrier integrity [54].

Changes in the GM's composition and function, referred to as dysbiosis, have been associated with various metabolic and immune-related diseases, such as obesity, diabetes, inflammatory bowel disease, hepatic diseases, colorectal cancer, and allergy [55]. Dysbiosis is characterized by an imbalance between beneficial and pathogenic bacteria resulting from an alteration in bacterial species. Long-term exposure to particulate matter (PM_2.5), nitrogen oxides (NO_x), and ozone (O₃) are correlated to high risk for obesity, glucose dysregulation, and type 2 diabetes [56,57]. It is believed that these may involve elevated levels of inflammation throughout the body, changes in the metabolism of adipose tissue, as well as effects on the GM [56]. Indeed, the exposure to near-roadway air pollution with high levels of NO_x was correlated with the relative abundance of gut bacteria that have been associated with obesity and altered metabolism [56,58].

3.2. Gut microbiota and EOCRC

Of the various cancer types on the rise among younger populations, a significant proportion are gastrointestinal related. The GM plays a critical role in maintaining the health of the gastrointestinal system. However, unhealthy diets, obesity, and sedentary lifestyles are becoming more common in successive generations, which raises the question of whether changes in GM, especially in early life, could interact with genetic factors to trigger the early onset cancers. Chronic physiological stress is known to affect the composition and function of the GM, potentially leading to increased gut permeability and inflammation, a precursor to numerous health issues [59,60]. Notably, studies revealed age-related disparities in the gut microbiome, with EOCRC patients exhibiting unique microbial imbalances compared to those diagnosed later in life [[44], [45], [46]]. Ongoing research consistently identifies new bacterial species linked CRC, highlighting the influence of external factors on the composition and behavior of these microbes [61]. Metagenomic analyses have identified certain bacteria frequently present in CRC patients, which suspected to contribute to cancer development including Bacteroides fragilis, Escherichia coli, Enterococcus faecalis, Streptococcus gallolyticus, and Morganella morganii [62,63].

Dietary interventions have been shown to have a significant effect on GM composition and subsequently health outcomes. For example, increased dietary fibers have been associated with enhanced microbial diversity [64]. Specific probiotic supplements particularly combinations of Bifidobacterium longum, B. bifidum, Lactobacillus acidophilus, and L. plantarum, have demonstrated the potential to suppress colorectal cancer cell growth in vitro [65]. Furthermore, in-vitro experiments have shown that certain probiotics regimens, especially when paired with cancer therapeutics like 5-fluorouracil, may hinder the progression from adenoma to carcinoma [66]. Additionally, fecal transplants from CRC patients to mice resulted in increased cellular proliferation and tumorigenesis, reinforcing the suspected link between GM composition and cancer development [67]. These studies collectively suggest that there is an association between the GM composition and CRC tumrogenesis [40]. Despite robust empirical evidence tying dysbiosis to cancerous processes, the definition of a ‘healthy' GM remains indistinct. In summary, GM imbalances and the metabolites they produce are instrumental in fostering chronic inflammation that can lead to CRC [46]. Such inflammation can result in further microbial imbalances and the proliferation of carcinogenic bacteria [46,68], reinforcing the hypothesis that environmental impacts on GM during early life stages may be critical determinants of CRC in younger demographics. Table .1 summarizes the key findings on the early life exposure and their influence on gut microbiota.

Table 1.

Key points of early life exposure impact on Gut Microbiota and correlation with EOCRC.

Key Points	References
Accumulation of both internal and external factors throughout a person's life progressively increase their risk of developing cancer over time.	[24]
Early life factors include delivery mode, nutritional intake, antibiotics use, childhood, and early adulthood exposures, diet, smoking, chronic health conditions, and environmental exposures	[9,[25], [26], [27], [28], [29]]
Certain bacteria in the gut can produce toxins, such as secondary bile acids, that have been linked to an increased risk of colorectal cancer.	[69,70]
There is a strong link between modifications in the host's microbiome and the development of EOCRC	[34]
The gut microbiota has a key role in regulating inflammation in the gut. Imbalance in the gut microbiota (Dysbiosis), can lead to chronic inflammation, which is a known risk factor for EOCRC	[71,72]
Disturbances in the gut microbiota, including changes in composition and function, are major contributors to the development of environmentally induced colorectal cancer at different ages	[9,[39], [40], [41], [42], [43], [44], [45], [46], [47]]
EOCRC patients exhibiting unique microbial imbalances compared to those diagnosed later in life	[44]
Specific probiotic supplements have demonstrated the potential to suppress colorectal cancer cell growth in vitro	[65]

3.3. Environmental exposures influence on the GM

When humans are born, they start to acquire bacteria and continue to be exposed to bacteria from their surroundings throughout their lives [73,74]. There is increasing evidence suggesting that the acquisition and development of a healthy microbiota in the infant are pivotal to exerting long-lasting beneficial effects in disease prevention [75]. It is thought that the maternal vaginal, oral, gut and skin microbial reservoir contribute largely to the infant microbial development [76]. Several postpartum factors do determine the infant gut microbial colonization such as the mode of delivery, the type of feeding, maternal diet, and maternal health [77]. As the infant grows, the composition of the GM changes over time as a result of internal and external factors [78], but it usually remains stable despite ongoing exposures, referred to as “resilience phenomenon”, which aims to keep key species stable for extended periods [[79], [80], [81]]. Fig. 2 represents the dynamic equilibrium of the microbiota composition, which fluctuates on a daily basis due to regular, minor disturbances. Under typical conditions, the microbiota demonstrates resilience, absorbing variations and maintaining a stable, healthy state characterized by adaptability and regulatory homeostasis. However, when subjected to prolonged or severe disturbances, the microbiota reaches a critical, unstable state, termed a tipping point. At this juncture, the system can diverge towards two distinct outcomes: (A) If the disturbance continues or the system's response is maladaptive, the microbiota may transition to an unhealthy composition. This shift can disrupt the balance and lead to dysbiosis, potentially triggering disease states [52,81,82]. (B) Alternatively, the system may adapt to the disturbance, settling into a new, alternate stable state. This state, while different from the original, becomes the established equilibrium for the microbiota, demonstrating that the system can find a new equilibrium after significant changes [81]. This model highlights the importance of understanding the factors that contribute to the resilience of microbiota and the consequences of its disruption, as well as the potential for recovery and establishment of a new, healthy baseline.

Fig. 2.

Homeostasis of gut microbiota (GM) as a response to external and internal factors. The microbiota composition fluctuates daily within a healthy range. Severe disturbances, however, can push it to an unstable state—a tipping point. In this critical phase, the composition may shift to an unhealthy state, leading to disease, or adapt to establish a stable, altered ‘new normal' as its baseline. Adapted from Ref. [81].

Humana are continually exposed to hundreds chemicals from the environmental, primarily through digestion and inhalation. The level of more than 300 of these chemicals or their metabolites have been detected in different human biological specimens [83]. The gut microbiome plays a significant role in metabolizing dietary components and xenobiotics into bioactive molecules that can impact health by altering microbiota growth and balance, along with having inherent inflammatory and carcinogenic properties [2,[84], [85], [86], [87]]. The interaction between these environmental factors and the GM is a key area of research, particularly considering the pervasive use of synthetic chemicals in industrial and agricultural settings, as well as the implications of air pollution and pesticides [[88], [89], [90], [91]]. These practices have led to environmental contamination, prompting global concern over potential health effects [20,85]. A key area of research is the impact of dietary habits since younger age group on GM, particularly the effects of modern Western diet. Research has indicated that this type of diet can markedly decrease the diversity of GM, while simultaneously increasing the prevalence of certain bacteria known to secrete harmful metabolites like N-nitroso compounds and hydrogen sulfide. Such metabolites are linked to carcinogenesis via mechanisms involving genetic mutations and the alkylation of DNA [[92], [93], [94]].

4. Can environmental exposure since 1950 explain the increased incidence of EOCRC?

To investigate the link between early-life environmental factors and the rising occurrence of EOCRC in individuals born after 1950, it is essential to analyze the changes that have taken place during this specific time frame. An extensive examination of available research highlights three significant environmental changes that have been notable since 1950: air pollution, pesticide use, and global warming. These factors will be succinctly summarized and explored in the subsequent sections. However, given the scope of this review, it is not feasible to comprehensively cover all these aspects. Instead, this review will concentrate on providing a summary of existing evidence regarding their association with colorectal cancer.

4.1. Air pollution

4.1.1. Air pollution since 1950

The industrial revolution, which started in the late 18th century in the UK and then spread to Europe and North America, caused a significant increase in coal combustion in cities, resulting in the emission of pollutants such as sulfur oxides (SO_x), nitrogen oxides (NO_x), ammonia (NH₃), and smoke [95]. This had negative effects on human health, particularly those living in urban areas. However, it was not until the 1950s that the use of fossil fuels for generating electricity, steel production, transportation, and manufacturing experienced a significant surge. This led to a significant increase in the amount of CO₂ being released into the atmosphere, reaching a global emission level of 6 billion tons per year by that time [25]. The burning of coal for warmth and cooking by a rapidly growing urban population of factory workers also contributed to high emissions.

Moreover, since 1950, there has been a significant increase in the world population, urban population, and the number of motor vehicles. The rise in the number of motor vehicles has been a significant contributor to air pollution, with transportation emissions being a primary source of carbon dioxide (CO₂), NO_x, and particulate matter (PM). According to the International Energy Agency, there were over 1.2 billion motor vehicles in use globally in 2016, and this number is expected to reach 2 billion by 2040. Transportation is the dominant source of most criteria air pollutants (carbon monoxide (CO), NO_x, ozone (O₃), volatile organic compounds (VOCs), lead (Pb), and PM) except SO₂. In addition, improvement in vehicle manufacturing has reduced CO and Pb (leaded gasoline phased out) since late 1970s. Country-scale emissions of SO₂ were close to their maximum in 1950. Soot and SO_x were the main chemical constituents in smog, which was problematic in many industrialized cities during the first half of the 20th century including the catastrophic event in London in 1952 and the deadly smog episode in Donora, Pennsylvania in 1948 [96]. Of course, SO₂ emission is still high from industrial activities, particularly those utilizing coal. However, there has been a world-wide reduction in the use of coal and shifting to cleaner and more renewable options.

4.1.2. Air pollutants as carcinogens in EOCRC

Air pollution, caused by various contaminants in the atmosphere, is extensively studied and linked to lung cancer. Ongoing research is also investigating its connection to CRC. Air pollution refers to the presence of a wide range of contaminants in the atmosphere. It comes in many forms including aerosols, ashes, dusts, gases, smoke, haze, photochemical products, and toxic compounds like POPs, and even unpleasant odors. They have harmful effects to living organisms or can cause a change in the climate which in turn will negatively affect the human life/health as it will be discussed later. Air pollution is one of the most serious environmental issues directly affecting public health as well as the earth's climate and ecosystems [97]. Human activities in industry, agriculture, transportation, etc. are the main sources of air pollution along with natural sources such as volcanic eruptions, sandstorms particularly in arid and semi-arid areas, and wildfires which have much lower effects as compared to anthropogenic activities [98]. Generally, air pollutants may include SO_x, NO_x, CO, O₃, VOC_s, volatile forms of heavy metals (e.g., Hg, Pb, As), airborne PM, etc. According to the World Health Organization (WHO), 99 % of the population all over the world are breathing air that surpasses WHO standards and sometimes even contains high levels of pollutants, with the highest exposure levels in low- and middle-income countries. Additionally, air contaminants including greenhouse gases e.g. CO₂, methane (CH₄), and nitrous oxide (N₂O) are known to trap heat in the lower atmosphere (i.e., troposphere) and contribute to global warming and consequently climate change. This increase in temperature has a variety of impacts on ecosystems. This includes melting glaciers, rising sea levels, and changes in precipitation patterns, which can lead to droughts, floods, and wildfires, affecting human health directly and indirectly. Air pollutants also have direct impacts on ecosystems, including acid rain, which can harm plants, animals, and aquatic life. This can further lead to biodiversity loss and changes in the distribution of plant and animal species. Air pollutants reduce air quality, which can harm human health and the health of animals that rely on clean air. According to recent data from a prospective cohort study involving 623,048 participants over a period of 22 years, a positive association was reported between nitrogen dioxide (NO₂) exposure and increased mortality from CRC, with a hazard ratio (HR) of 1.06 per 6.5 parts per billion (ppb) [99]. Two main mechanisms were proposed to explain how air pollution might affect the progress of different types of cancers; oxidative stress and inflammation. The first mechanism is related to DNA damage caused by reactive oxygen species (ROS) generated in response to particulate matter and nitrogen-containing pollutants, which can promote cell proliferation, genetic instability, and mutations. The second mechanism involves the release of proinflammatory cytokines, such as interleukin-6 and interleukin-8, which can be elevated as a result of exposure to gaseous and particulate pollutants [100]. There are recent evidences linking air pollution to metabolic syndrome, including insulin resistance and diabetes mellitus, which are considered significant risk factors for CRC [101].

A few studies have provided preliminary evidences associating air pollution with the initiation of CRC [[102], [103], [104]]. However, there is no insufficient epidemiological data to establish a definitive connection between exposure to ambient air pollutants and the risk of CRC [105,106]. The lack of conclusive evidence regarding this association may be attributed to the prolonged duration required for exposure to lead to the development of cancer. It is noteworthy that the majority of existing research on the relationship between air pollution and CRC primarily focuses on the impact of PM on cancer progression which is discussed below.

4.1.3. Fine particulate matter (PM_2.5) and EOCRC

Fine particulate matter (PM_2.5), subset of aerosol pollution, refers to particles with a diameter of 2.5 μm or less. It consists of tiny particles suspended in the air that can be inhaled into the lungs and cause adverse health effects. Aerosol pollution, on the other hand, refers more broadly to the presence of any type of small particle or liquid droplet in the air, regardless of its size. This can include particles larger than 2.5 μm, such as pollen or dust, as well as liquid droplets such as those found in fog or mist. PM_2.5 is considered particularly harmful because of its small size, which allows it to penetrate deep into the lungs (i.e., air sacs or alveoli) and potentially enter the bloodstream. Long-term exposure to PM_2.5 has been linked to a variety of health problems, including heart disease, lung cancer, and respiratory illnesses.

Long-term exposure to outdoor PM_2.5, is the leading environmental risk factor for human health, accounting for an estimated 4.1 million deaths worldwide, or 7.3 % of all global deaths in 2019 [105,106]. In Europe and the Eastern Mediterranean, up to 1 million people die prematurely each year due to air pollution [107]. PM_2.5 is mainly composed of inorganic ions, carbonaceous compounds (black carbon), and mineral dust and is emitted by various sources, including direct emissions (like forest fires, agricultural waste burning, uncontrolled waste incineration, and windblown mineral dust from arid areas) and generation as secondary air pollutants from atmospheric chemical reactions.

The interest in studying the effects of PM on CRC, particularly in younger individuals, is growing. Studies have shown that exposure to PM_2.5, black carbon/soot, and organic carbon in ambient air pollution can increase the risk of developing CRC [14,108] and increase mortality [99,[109], [110], [111]], regardless of age. PM can reach the gut through contaminated food and water [112], clearance from the lungs [112], or bloodstream [113]. In an individual on a typical Western diet, an estimated 10¹²-10¹⁴ particles reach the gut daily, with an estimated high mucosal uptake [114]. Once in the gut, PM can cause DNA damage, chronic inflammation, and alter the function of the gut microbiota, promoting tumor growth and abnormal cell growth [[115], [116], [117]]. PM_2.5 exposure has been shown to induce circulating inflammatory cytokines, ROS, and cell death in colonic epithelial cells in a dose-dependent manner [[118], [119], [120]].

PM_2.5 is considered a group 1 carcinogen for lung cancer [121], but its potential role in gastrointestinal cancer is still being studied. A recent study found markers of oxidative stress in fecal samples of individuals who consumed red meat [122], which contains carcinogenic compounds that are also found in environmental sources like cigarette smoke, dust, and exhausts of automobile engines. This suggests that people exposed to high levels of these pollutants may have an increased risk of CRC. The impact of ingested PM on GM is still being studied [123], but evidence suggests that PM does alter the GM composition and can induce dysbiosis and inflammation [36,124]. The exact mechanism of how PM_2.5 exposure leads to CRC is not yet clear, but a meta-analysis found consistent evidence of a positive association between PM_2.5 exposure and CRC [111]. A study found that that each 10 μg/m³ increase in PM_2.5 concentration corresponds to an 8 % increase in the risk of CRC [101] through different mechanisms, most importantly GM disturbances.

Overall, ingested and inhaled PM can significantly alter the GM composition and expose the intestine to harmful metabolites that may induce carcinogenesis and chronic inflammation [125,126]. A meta-analysis involved 30 cohort studies with over 1.0 million cases across 14 countries demonstrated that significant hazardous influences of PM_2.5 were noticed for lung cancer mortality and non-lung cancer mortality including liver cancer, CRC, bladder cancer, and kidney cancer, respectively [127]. In a recent study that investigated the association between CRC and proximity to industries, it was found that CRC is detected near industries overall for all distances. The excess risk was higher near industries that released pollution to air rather than water, and industries such as metal, glass, chemical, food, and organic solvents showed excess risks. The study also found an increased risk near plants releasing nonylphenol, antimony, naphthalene, and manganese [128]. Similar results were reported in other studies where individuals living near industrial facilities were exposed to numerous carcinogens and toxic substances, including PCBs, arsenic, PM₁₀, POPs, and metalworking fluids, which may contribute to the development of CRC [129,130].

4.2. Pesticide utilization

4.2.1. Pesticide utilization since 1950

Pesticides include chemicals that acts as insecticides, herbicides, and fungicides.

The 20th century witnessed a significant surge in the production and utilization of such synthetic pesticides, which increased by 50 times since 1950. This era, often referred to as the “pesticide era” or the golden years for farmers, saw widespread pesticide usage leading to improved agricultural yields. The expenditure on pesticides also experienced a tenfold increase between 1945 and 1972. For instance, in 1952, herbicides were applied to 11 percent of corn fields and 5 percent of cotton fields. By 1982, these figures had risen dramatically to 95 percent for corn and 93 percent for cotton [131,132]. However, the use of pesticides presents environmental challenges as a significant portion drifts away from their intended target, accumulating in unintended species, air, water, and soil [132].

This raises concerns regarding the increased incidence of environmentally induced CRC, which warrants further investigation.

Exposure to pesticides can occur through occupational activities such as farming, pesticide application, and pesticide manufacturing. Pesticides that are applied to farms or yards can persist in the environment for longer periods than intended. They may remain on the surface soil, leading to their spread through dust, runoff, or they may leach into the deeper soil layers, potentially reaching groundwater sources and, in some cases, even drinking water.

Numerous studies have examined the relationship between CRC risk and pesticide exposures, but the results have been inconclusive. This is primarily due to the fact that the majority of these studies are epidemiological in nature, relying on self-reporting methods to assess CRC risk, rather than directly measuring the levels or concentrations of pesticides in biological samples. Epidemiological studies have limitations, as they depend on individuals' self-reporting accuracy. On the other hand, studies that analyze specific or multiple pesticide metabolites in human samples offer a more objective approach by directly measuring the presence of pesticides in biological samples. Soliman et al. reported an increase in the serum level of pesticides in CRC patients [133]. There are other studies that showed a strong association between the exposure to pesticide especially by ingestion of pesticide contaminated meat and the risk of CRC Furthermore, an increase in incidence of CRC was reported in the last few decades especially in regions that higher rates of pesticides usage due to loose environmental regulations [104]. It was found that pesticide acts through alteration of microbiota composition both in human and animals [19]. A recent systematic review [131] has analyzed existing literatures and summarized the findings where pesticides have been classified into 3 categories according to existing evidences as shown in Table 2. In order to comprehend the underlying mechanism of the observed association, it is important to consider that many of the pesticides utilized are known to be endocrine disrupting chemicals (EDCs). Therefore, further exploration into the impact of EDCs on the initiation of CRC will be discussed.

Table 2.

Pesticides categories according to their association with CRC according to Ref. [131].

Category	Reasons	Example
Low concern	1- No significant association	Fonofos, aldrin, toxaphene, and heptachlor
	2- Inverse association
	3- Significant positive association but have been banned/severely restricted in the US and other countries
Moderate concerns	Significant positive association and have been banned or severely restricted in the US and other countries but residue found in soil, food and water	Aldicarb and dieldrin
	Both positive and inverse associations	dichlorodiphenyltrichloroethane (DDT), lindane, 2,4-Dichlorophenoxyacetic acid (2,4-D), alachlor, chlordane, methylene cyclopropyl acetic acid (MCPA)
High concerns	Significant positive associations and have not been banned in the US	Terbufos, dicamba, trifluralin, EPTC, imazethapyr, chlorpyrifos, carbaryl, pendimethalin, and acetochlor

4.2.2. Endocrine disturbing chemicals (EDCs)

Among all factors that were shown to affect the GM composition and function,Endocrine disturbing chemicals (EDCs) are considered the most critical [78]. They are defined as natural and synthetic molecules that interfere with the action of hormones [134]. EDCs are commonly released during the production and use of synthetic materials such as plastics, pesticides, electronic waste, metals, food additives, and personal care products. They are present throughout the environment, and humans are exposed to them through various means including consuming contaminated food and water, inhalation, and through skin. Food contamination is considered the main route of exposure which could be either directly from pesticide contaminated food or when they are released from food packaging. EDCs can also be transferred from mothers to their fetuses and infants through the placenta (i.e., fetal-placental barrier) and breast milk, respectively. The metabolites resulted from the microbial metabolism of EDCs do impact the host overall health and immunity [135]. Although the effect of EDCs is mainly on the reproductive system, puberty, embryonic development, and sex differentiation, there is also growing concern that EDCs may be linked to metabolic disorders through the microbiota influence [136,137]. Children and developing fetuses are particularly vulnerable to the effects of EDCs and exposure to these chemicals is thought to increase the risk of metabolic disorders and non-communicable diseases later in life [18,136,138,139]. In fact, a triad was proposed for the EDC impact on human which goes through an interaction between the host genotype, phenotype and GM [140]. EDCs was found to disturb microbial communities in favor of unhealthy species that are associated with immune disturbances and diseases progression. Furthermore, recent studies have shown that EDCs induce epigenetic changes which modify the gene expression without causing DNA mutation [141]. Bisphenol A (BPA) along with dioxins and DDT are the most widely studied EDCs in terms of epigenetic changes [[142], [143], [144], [145], [146]]. In addition, the epigenetic changes induced by EDC are thought to manifest later in life despite early life exposure [147] which might support an association with EOCRC. Overall, EDCs have been proved to play an important role in the development of CRC through different mechanisms such as modification of the inflammatory profile, endocrine homeostasis, and epithelial junctions [14,36].

Microplastic (MP) particles are another element attracting attention in this regard. Research has documented the presence of MP particles in various food products, indicating the extensive exposure within the population [148,149]. Despite their widespread presence, the potential risks posed by MPs remain poorly understood [150]. Typically perceived as chemically inert due to their size as well as chemical nature, plastics have shown unexpected behaviors under gastrointestinal conditions. Simulation studies indicate that ingested MPs can degrade into smaller pieces during gastrointestinal transit, with the stomach's acidic environment potentially transforming them into more reactive forms. The inherent irritability of MPs, coupled with their role as vectors for environmental contaminants including plasticizers, flame retardants, and unreacted monomers due to incomplete polymerization, can lead to adverse health effects [151]. In recent studies, MP particles have been found in greater quantities in tissue biopsies from CRC patients compared to healthy individuals [152]. Experiments simulating the digestion of polyethylene terephthalate (PET) by the GM revealed that PET not only undergoes degradation, but also significantly alters the composition and diversity of the GM within 72 h across different segments of the simulated colon [153,154]. Moreover, the size of MP particles found at tumor sites was larger than those in adjacent normal tissues, suggesting a potential correlation that warrants further investigation to establish a definitive link.

4.3. Global warming

4.3.1. Global warming since 1950

Since the late 1950s, the global average surface temperature has exhibited a rise of 0.6 °C. According to the fifth assessment report of the Intergovernmental Panel on Climate Change (IPCC), human activities and associated emissions account for approximately 100 % of the observed warming since 1950. Ongoing analyses conducted by the scientific team at NASA's Goddard Institute for Space Studies (GISS) indicate that the average global temperature on Earth has increased by a minimum of 1.1 °C (1.9 °F) since 1880. The majority of this temperature rise has occurred from 1975 onwards, with a rate of approximately 0.15–0.20 °C per decade [155].

The projections presented in the fourth Assessment Report (AR4) regarding future climate changes until 2100 demonstrate a high level of confidence in certain aspects [156]. These include a pronounced elevation in maximum temperature and the frequency of hot days, as well as an elevation in minimum temperature and a reduction in the occurrence of cold days, both considered highly probable. Additionally, it is highly likely that there will be an intensification in the duration and severity of warm spells, heatwaves, and precipitation events. Furthermore, the likelihood of experiencing droughts or aridity, alterations in the intensity, frequency, and duration of tropical cyclone activity, and an increase in extreme sea levels (excluding tsunamis) is also substantial [156]. The repercussions associated with escalating temperatures encompass a wide range of adverse effects, such as soil degradation, diminished agricultural productivity, desertification, loss of biodiversity, degradation of ecosystems, depletion of freshwater resources, and acidification of oceans [157,158].

4.3.2. Global warming and EOCRC

A neonate born today will experience a world that is 1+°C warmer than the pre-industrial era, which will have a significant impact on human health throughout their lifetime [159]. Global warming and consequently climate change have already resulted in extreme weather events, infectious diseases, and food security concerns. If left unchecked, climate change will continue to affect the health of both current and future generations [160]. The increase in environmental heat is known to modulate the core temperature of the human body, which in turn regulates the structure and function of enzymes, proteins, and various regulatory pathways. Gut function in vertebrates is also temperature-dependent, and changes in temperature can influence the function and composition of the GM, which in turn can affect digestion and metabolic responses to both nutrients and xenobiotics. It is worth mentioning that the human GM has thermotolerant and temperature-sensitive species, which are critical to determine the impact of short-term weather changes and long-term climate shifts on gut health and its relationship to overall individual's health. Experts predict that global warming will continue at a rate of 0.2 °C per decade if no action is taken. The recent increase in hot waves, with prolonged hot days in some areas, will cause heat stress to agriculture, animals, microbes, and humans. The rise in core body temperature due to environmental heat shifts the body's circulation from the gastrointestinal tract to the peripheries. This can impair the integrity of the intestinal wall and increase permeability [161]. Additionally, increasing temperatures are affecting the soil microbiota community and insect populations, leading to biodiversity loss and human health issues [162]. Global warming is exerting its effect on human health through other mechanisms as well. For example, plastic exposed to high temperatures leaches toxic molecules as MPs and phthalates into water, food, and soil, which can subsequently reach humans through the food chain and cause harm to human health and GM disturbances [163]. Furthermore, global warming causes evident endocrine disruption in humans and animals, which is thought to worsen the already known toxic effects of EDCs (Turner et al., 2016). Based on the available data, it is understood that climate change has the potential to elevate the risk of CRC by disturbing GM and amplifying exposure to carcinogens following extreme weather events like hurricanes and wildfires. Additionally, these events have been found to adversely affect access to cancer care, resulting in delays in diagnosis and ultimately impacting cancer survival rates [156]. Table 3 summarizes the key to findings on the development of EOCRC and the environmental exposure.

Table 3.

Key points of findings on the impact of environmental exposures on EOCRC development.

Key Points	References
Long-term exposure to PM2.5, NOx, and O3 is correlated with changes in the gut microbiota	[56]
A modern Western diet adopted from a young age reduces gut microbiota diversity and increases harmful bacteria, which can produce cancer-linked metabolites	[[92], [93], [94]]
Prolonged or severe disturbances in the environmental factors can lead to an unhealthy composition of the gut microbiota	[81]
Exposure to environmental pollutants, such as heavy metals and pesticides, can disrupt the gut microbiota and contribute to the development of gastrointestinal diseases through different mechanisms	[[88], [89], [90], [91]]
Endocrine-disrupting chemicals (EDCs) found in air pollutants, such as phthalates, bisphenol A (BPA), PCBs, PFAS, and organochlorine pesticides, can increase the risk of EOCRC, through their endocrine-disrupting properties and effects on inflammatory pathways and immune function.	[[142], [143], [144], [145], [146]].
Microplastic (MP) particles, may pose a risk for EOCRC due to their potential degradation in the gastrointestinal tract, release of reactive forms, and role as carriers of environmental contaminants, potentially impacting gut microbiota composition	[153,154]
MP particles have been found in greater quantities in tissue biopsies from CRC patients compared to healthy individuals	[152]
Global warming, with its associated climate changes, may increase the risk of EOCRC by disrupting the gut microbiota and amplifying exposure to carcinogens, particularly following extreme weather events like hurricanes and wildfires, which can also impact access to cancer care	[156,163].

4.4. International Agency for Research on Cancer (IARC) monograph

Usually, these evidences are considered by the International Agency for Research on Cancer (IARC) to evaluate the carcinogenicity of these chemicals. IARC has established the Monographs Program in 1970 to categorize various substances, including chemicals, biological agents, mixtures, specific occupations, and lifestyle factors, according to their ability to cause cancer in humans based on available evidence. The program is carried out by expert scientists from different fields who evaluate published studies and determine the strength of the evidence for a specific agent's carcinogenicity. The IARC Monographs Program has evaluated more than 1000 agents, and classified them according to evidences of their carcinogenetic into 4 groups as shown in Table 4 [164]. The list is periodically updated to keep it current. However, it is important to note that labeling a substance as a carcinogen does not necessarily mean that it will cause cancer as many factors affect the development of cancer, including the amount and duration of exposure and an individual's genetic background. There are several environmental pollutants that have been listed as Group 1 carcinogens according to the latest monograph.

Table 4.

Agents classified by the IARC monographs.

Group	Carcinogenicity	No. of agents
Group 1	Carcinogenic to humans	126 agents
Group 2A	Probably carcinogenic to humans	94 agents
Group 2B	Possibly carcinogenic to humans	322 agents
Group 3	Not classifiable as to its carcinogenicity to humans	500 agents

It is important to note that while many of the chemicals and exposures discussed in this review have strong evidence to be classified as Group 1 or Group 2A carcinogens for lung cancer and other types of upper respiratory tract cancers, they have not been conclusively linked to CRC [164]. Conversely, the Group 1 category for CRC includes factors such as alcoholic beverages, consumption of processed meat, tobacco smoking, and X- and gamma-radiation. This highlights the need for further biological and epidemiological studies in both humans and animals to better understand the long-term effects of exposure to these chemicals/factors on the growth of cancer cells in the colon and rectum. Such studies will also help to determine if early-life exposure can account for the increasing incidence of environmentally induced CRC.

5. Limitations and future research direction

Understanding the potential mechanisms linking environmental factors to changes in the GM and increased risk of EOCRC are crucial. However, there is a need to articulate the limitations of current studies more explicitly. These limitations include the observational nature of many studies, the complexity of environmental exposures, and individual variability in the gut microbiota. Future research should focus on longitudinal human studies that can establish causality more effectively and unravel the long-term impacts of environmental factors on the GM. It would also be beneficial to identify specific microbial signatures that could serve as biomarkers for EOCRC risk. Moreover, understanding the interplay between genetics and the environment in modulating the GM could lead to personalized interventions. Regarding interventions, the manipulation of the GM presents a promising avenue to reduce the incidence of EOCRC, however such interventions must be approached with caution. The complexity of the gut ecosystem and its interactions with the host mean that any alterations to the microbiome must be carefully controlled and monitored. Clinical trials are essential to validate the safety and efficacy of microbiome-targeted therapies, ensuring that interventions do not disrupt the delicate balance of the GM or inadvertently promote dysbiosis. By conducting well-designed clinical trials, we can also clarify the therapeutic window and dosage of probiotics or prebiotics, understand the longevity of the treatment effects, and identify any potential side effects or unintended consequences.

6. Conclusion

Colorectal cancer in individuals aged 18–49 suggests prolonged exposure in early life. While genetic factors play a role in EOCRC, environmental factors have been found to be more significant in determining disease risk. This highlights the importance of focusing on environmental factors in cancer prevention strategies. The relationship between genetic and environmental factors in EOCRC is complex and requires further investigation. Several potential factors could explain the increasing incidence of EOCRC, such as obesity, sedentary lifestyle, physical and social stress, and environmental pollution from air pollution, pesticide use, water, and soil contamination. Convincing evidence is available for the association between GM disturbances and EOCRC incidence, as well as between environmental pollution and GM disturbances, however there is no strong and direct evidence linking the environmental pollution to increase incidence of EOCRC. The mechanisms underlying how environmental pollutants such as PM and EDCs impact the GM are still being studied.

A multi-faceted approach that addresses rising EOCRC incidence through targeted policy changes and interventions is necessary. This includes stricter regulations on air pollutant emissions and pesticide use reduction and climate change mitigation strategies to minimize exposure to harmful environmental factors. Better management of EDCs and MPs and updated dietary guidelines that promote GM health will also help reduce EOCRC risk. Early-life interventions, such as those designed to protect pregnant women, infants, and young children from harmful exposures, should be given special attention due to the importance of early-life events in shaping future health. More research funding is needed to better understand the environmental drivers of EOCRC. Specifically, funding should go towards longitudinal studies of EOCRC beginning in early life to understand key risk factors, biomarkers, and potential interventions. Longitudinal studies are necessary to establish a causal link between environmental pollution and EOCRC. Furthermore, it is essential to take systemic international measures to reduce environmental pollution, mitigate climate change, and thereby frequently improve health and preserve biodiversity. To address this intricate web of relationships between environmental factors and EOCRC, a multi-sectoral approach involving collaboration between governments, industry, academia, and civil society is needed, and calls for implementation for a healthier environment for all.

Funding statement

No funds were received for this manuscript.

Availability of data and materials

Not applicable.

CRediT authorship contribution statement

Adhari AlZaabi: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Funding acquisition, Formal analysis, Data curation, Conceptualization. Hussein A. Younus: Writing – review & editing, Writing – original draft. Hassan A. Al-Reasi: Writing – review & editing, Writing – original draft, Visualization, Validation, Conceptualization. Rashid AlHajri: Writing – review & editing, Writing – original draft, Visualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.