Open access peer-reviewed chapter - ONLINE FIRST
Abstract
A measurable and/or observable change in a biological or biochemical reaction, encompassing behavioral alterations as well as molecular to physiological levels, is referred to as a biomarker. Biomarker responses must be ecologically meaningful and show exposure to the harmful consequences of environmental stressors. When assessing the condition of an ecosystem, biomarkers are regarded as early warning systems. They are useful for evaluating in-situ chemical exposure and the harmful impacts of contaminants on biota. Although they are assessed on an individual basis, the purpose of their reactions is to forecast population-level consequences. We hope to give a broad definition of biomarkers and xenobiotics in this chapter, as well as an overview of the processes involved in their biotransformation and detoxification in aquatic organisms.
Keywords
- ecotoxicology
- aquatic organism
- biomarkers
- pollutant
- xenobiotic
1. Introduction
Biomarkers in ecotoxicology have a clear definition. When we talk about biomarkers, it means that we want to define a series of indicators that help to evaluate the toxicity of a chemical compound at different biological levels. Certain biomarkers are used to indicate changes in the physiological status of aquatic animals exposed to environmental pollutants. Some others are useful for monitoring biochemical levels [1, 2]. Moreover, molecular biomarkers reflect responses at cellular and molecular levels in organisms exposed to xenobiotics. Molecular biomarkers include the analysis of gene expression profiles, protein synthesis, or DNA damage in finfish and shellfish exposed to xenobiotics [2].
Changes in growth performance, reproduction success, adaptability, feeding, and behavior in aquatic animals after xenobiotic exposure are physiological biomarkers. Changes in analytes, metabolites, and enzyme activities in tissues and biological fluids such as blood, hemolymph, and cerebrospinal fluid are categorized as biochemical biomarkers. Cellular biomarkers focus on changes in cellular structures, functions, morphology, and membrane integrity. Oxidative biomarkers are used to assay the formation of reactive oxygen species (ROS) and the status of cellular antioxidant defenses [2, 3, 4, 5].
We know that biomarkers are reliable indicators for assessing the biological responses of aquatic organisms to xenobiotic exposure. These indicators may provide valuable information about the efficiency of detoxification pathways and the overall health status of aquatic organisms. Therefore, the use of biomarkers for comprehensive evaluation and monitoring of the effects of xenobiotics on aquatic ecosystems is very common. In many cases, the integration of different biomarkers helps researchers to better understand the mechanisms of detoxification and biotransformation [6, 7].
In this chapter, we will first offer a general definition of xenobiotics and outline their biotransformation and detoxification processes. Subsequently, an introduction to biomarkers at various biological levels will be provided.
2. Xenobiotic
Xenobiotics include all materials and compounds that are unknown to living organisms. Most xenobiotics are man-made substances that have various uses. Pharmaceutical materials, agrochemical compounds, crude oil, petroleum derivatives, paint and resin, plastic polymers, industrial and household detergents, cosmetics and health products, etc., are known as xenobiotics (Figure 1). Xenobiotics typically enter the environment, particularly aquatic ecosystems, through industrial, urban, and agricultural wastewater, as well as surface runoff, both intentionally and unintentionally. Therefore, their entry into the environment can be considered a serious threat to the life of aquatic organisms and ecosystems. These substances can enter an animal’s body through the respiratory tract or gills, skin, and digestive system. Xenobiotic can easily cross biological barriers and enter the blood, cells, and vital tissues due to the hydrophobic and lipophilic nature of these compounds [8].
Figure 1.
Most common xenobiotics.
In response to the entry of xenobiotics into the body of aquatic animals, their detoxification and biotransformation systems activate, attempting to convert these compounds into more polar, simpler, and less toxic substances for elimination from the organism’s body. Toxicology studies show that many vital organs, such as the liver, kidneys, digestive system, and respiratory system, can play a significant role in the elimination of metabolites and xenobiotic compounds. Therefore, these organs must have the necessary mechanisms for detoxification and biotransformation of xenobiotic [9, 10, 11].
The metabolism of xenobiotic in these organs is often carried out during two stages, including phase I and phase II reactions. In phase I of detoxification, xenobiotic molecules may change their nature through oxidation, reduction, or hydrolysis reactions and become more reactive and water-soluble metabolites. Then these metabolites may enter the second phase reactions for further processing and detoxification. In this phase, the modified xenobiotic compound is combined and conjugated with endogenous molecules, such as glucuronic acid, sulfate, or glutathione. During the conjugation process, the solubility of xenobiotics and their metabolites in water increases and they are easily removed from the animal’s body.
Studies showed that xenobiotic can interact with specific receptors on cells, including the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), and peroxisome proliferator-activated receptors (PPARs) [12, 13]. The research displayed that the interaction of xenobiotic with cell receptors can cause the activation or inhibition of cell signaling pathways and the occurrence of cell response. In other words, following the binding of xenobiotic to specific receptors, gene expression of enzymes involved in xenobiotic metabolism and detoxification increases. Next, the process of biotransformation, detoxification, and removal of xenobiotic from the aquatic body begins.
The metabolism and biotransformation of xenobiotic is carried out by several enzymatic reactions with the aim of introducing or hiding functional groups that cause xenobiotic reactivity and further change [9, 10, 11].
In the second stage of metabolism and biotransformation of xenobiotics, the metabolites produced during the phase I metabolism process are eliminated from the aquatic body through conjugation reactions and combining with polar molecules. Phase II includes glucuronidation, sulfation and combining with glutathione.
In fish liver cells, the glucuronidation process plays an important role in the biotransformation of xenobiotics. During this process, xenobiotics are combined with glucuronic acid, a naturally occurring compound in the body, with the help of the enzyme UDP-glucuronosyltransferase (UGT). During the glucuronidation process, xenobiotics and their metabolites are converted into water-soluble compounds and excreted through urine or bile.
In the sulfation process, sulfate groups can be conjugated with xenobiotics, catalyzed by sulfotransferase enzymes. Then, the resulting sulfate compounds may also be excreted from the fish’s body through bile or urine.
The glutathione conjugation is an important biochemical process to remove xenobiotics and their metabolites from the body. Glutathione-S-transferase (GST) can accelerate the process of combining xenobiotics with glutathione. Next, the resulting product is easily excreted from the fish’s body through urine and bile [9, 10, 11].
2.1 Xenobiotic detoxification pathways
Studies showed that certain enzymes and molecular pathways may be activated during the metabolism and detoxification of xenobiotics in aquatic animals [14, 15, 16].
Exposure to different pollutants can induce the Nrf2 pathway. In this situation, Nrf2 may act as an enhancer, and bind to antioxidant response elements (AREs) in the promoter regions of target genes (Figure 2).
Figure 2.
Nrf2 pathways.
This phenomenon can affect the expression levels of antioxidant enzymes and phase II detoxification enzymes. Thus, a significant increase in the expression of their genes can mitigate oxidative stress induced by ROS production [16].
Kong et al. studied the mechanisms of Nrf2 and NF-κB signaling pathways in inflammation in
Studies showed that AhR plays an important role in the cellular uptake of certain xenobiotics. Polycyclic aromatic hydrocarbons (PAHs) and other aromatic compounds may bind to AhR and cross the nuclear membrane. Subsequently, this complex can translocate to the nucleus and bind to response sequence elements. It can then act as either an enhancer or a suppressor, altering the transcriptional process of target genes. Studies also showed that activation of the AhR pathway can induce the biosynthesis of cytochrome P450 enzymes, which are involved in the biotransformation of xenobiotics [17].
Similarly, PXR is another nuclear receptor protein that plays a vital role in the biotransformation and detoxification of xenobiotics. PXR is usually found in hepatocytes and intestinal cells. Xenobiotics can bind with PXR and translocate into the nucleus. Once there, this complex binds to response sequence elements in DNA, changing the transcriptional processes of target genes that encode cytochrome P450 enzymes [18, 19].
The function of CAR is similar to other nuclear receptors. CAR is commonly found in hepatocytes. The binding of xenobiotics to response sequence elements is mediated through CAR. The complex of CAR and xenobiotics can influence the expression of genes involved in drug metabolism and detoxification pathways [18, 20].
3. Biomarkers
In toxicology, scientists usually use various parameters to analyze the biological response of organisms to the toxicity of xenobiotics. These biological responses are known as biomarkers. In other words, biomarkers are measurable biological responses of aquatic organisms exposed to environmental pollutants. Ecotoxicologists believe that biomarkers must be sensitive enough to detect changes in aquatic organisms or ecosystems exposed to pollutants. Moreover, the more specific the biomarker, the more accurate the environmental and aquatic health monitoring will be. Additionally, the evaluation and measurement of biomarkers should be practical and feasible, capable of being conducted in both field and laboratory conditions [21, 22].
The biomarkers can be assayed at different levels, including molecular, cellular, tissue, organ, organism, population, and ecosystem levels. Moreover, biomarkers can be used to detect pollutants in the water environment.
Changes in different biomarkers, such as biochemical, physiological, histological, genetic, and behavioral parameters, can help scientists determine exposure periods, toxicity rates of xenobiotics, sensitivity of organisms, risks for aquatic organisms and ecosystems, and more [23, 24, 25]. In this part, we will discuss different biomarkers measured in aquatic organisms exposed to environmental contaminants (Figure 3).
Figure 3.
Different biomarkers that can be measured in aquatic organisms.
4. Types of biomarkers
4.1 Cellular biomarkers
Studying cell morphology, cellular proliferation, and differentiation rates, assessing enzyme activities involved in detoxification and biotransformation of xenobiotics, examining cellular stress response, acute phase proteins, cellular signaling pathways, cellular proliferation and apoptosis, and cellular damage and repair biomarkers are important aspects of cellular biomarkers [23, 26, 27]. In this section, we explain the main cellular biomarkers, while other cellular biomarkers are discussed in the following sections.
4.1.1 Morphology of cells
Changes in cellular structure can affect its functions. Changes in the morphology and structure of hepatocytes can disrupt a lot of biochemical and physiological processes, such as detoxification [28]. Furthermore, morphological changes in intestinal, kidney, and gill cells may cause osmoregulation dysfunction. Moreover, morphofunctional changes in the intestine of fish may affect metabolism and growth performance. Studies showed that some anemia may be related to morphological changes in cells of hematopoietic tissues such as the spleen and anterior part of the kidney of fish exposed to xenobiotics [29]. Silva Martinez reported some morphological changes in the cells of the kidneys of fish exposed to municipal sewage. Morphological changes in the gills of
4.1.2 Cellular proliferation and differentiation
Studies showed that cellular proliferation in different tissues of fish that are challenged with xenobiotics may be attributed to the regeneration process of damaged tissue [29]. Therefore, an increase in cellular proliferation rate can help tissues to recover themselves after exposure to xenobiotics [33]. However, the collapse in cellular proliferation may lead to tissue necrosis in aquatic animals exposed to different xenobiotics [34, 35].
Studies showed that disruption in stem cell differentiation in the embryos of aquatic animals exposed to xenobiotics may increase the teratogenicity rate in newborns [36, 37]. A lot of examples of teratogenic dysfunction were reported in fish exposed to hospital effluent [38], pesticides [36], and cyanobacteria extract [39].
4.1.3 Cell signaling pathway
Xenobiotics may activate or deactivate different cell signaling pathways. Therefore, understanding the mechanisms of xenobiotics on cell signaling pathways can help scientists mitigate the toxic effects of xenobiotics on aquatic animals. We know that cellular signaling pathways and their cascade of biochemical reactions play an essential role in regulating physiological functions within cells in response to oxidative stress.
Studies have shown that xenobiotics can affect the MAPK (mitogen-activated protein kinase) signaling pathway, inducing cascade biochemical reactions that play important roles in cell growth, differentiation, inflammation, and response to stress [40, 41]. Jia et al. [15] found that hydrogen peroxide could affect the MAPK signaling pathway, changing redox state, apoptosis, and endoplasmic reticulum stress in the hepatocytes of
Moreover, Tian et al. [42] showed that increased levels of ROS in cells can activate MAPK pathways, such as the c-Jun N-terminal kinase (JNK) and p38 MAPK pathways, which are necessary for responding to oxidative stress in
Studies have shown that exposure to xenobiotics can induce the Janus kinase (JAK) and signal transducer and activator of transcription 3 (STAT3) signaling pathway. Upon activation of JAK/STAT3 pathway, STAT proteins are phosphorylated by JAK. Subsequently, they act as transcription factors, regulating the expression of antioxidant enzyme genes. Therefore, activation of the JAK/STAT3 pathway can help manage oxidative stress in fish exposed to xenobiotics [46]. Moreover, Hu et al. [47] found that STAT3 activation can guarantee cell survival in grass carp (
4.1.4 Autophagy and apoptosis
Studies showed that autophagy and apoptosis usually occur after inducing signaling pathways of oxidative stress in finfish and shellfish exposed to environmental pollution and toxic materials [49, 50]. Increased autophagy and apoptosis rates were reported in aquatic organisms exposed to different pollutants. The activation of autophagy and apoptosis mechanisms may be a strategy to remove damaged cells following exposure to xenobiotics [51].
4.2 Oxidative biomarkers
Oxidative biomarkers, including antioxidant and non-antioxidant enzymes, ROS contents, and peroxidation metabolites, are used to assess oxidative stress in aquatic organisms exposed to xenobiotics [8, 52]. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), etc., are important enzymes involved in neutralizing ROS and protecting cells from oxidative damage (Figure 4).
Figure 4.
Some enzymes of the endogenous antioxidant system.
The activity of glutathione reductase (GR) and glucose 6-phosphate dehydrogenase plays crucial roles in regenerating cellular glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH), respectively, which are necessary for continuing antioxidant enzyme activities [53, 54].
The collapse of cellular antioxidant defense and the imbalance between ROS and antioxidant agents can lead to cellular damage. Therefore, oxidative biomarkers can be used as cellular biomarkers for assessing the toxicity of pollutants in aquatic organisms and ecosystems [55].
Increasing or decreasing levels of antioxidant biomarkers indicate oxidative stress in finfish and shellfish exposed to different environmental pollutants [56]. Changes in oxidative biomarkers were reported in different species of crayfish, such as
4.3 Biochemical biomarkers
The biochemical biomarkers include measurements of enzyme activities, analytes, metabolite levels, and other biochemical parameters in the blood, hemolymph, biological fluid, and tissue extract. These parameters reflect some physiological responses to xenobiotic exposure at various levels. For example, the measurement of acetylcholinesterase activity (AChE) in nervous tissues, cerebrospinal fluid, serum, and hemolymph is a common biomarker for exposure to organophosphate and carbamate pesticides, crude oil hydrocarbons, as well as some heavy metals, etc. [62, 63]. A significant decrease in AChE activity was reported in zebrafish (
The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and lactate dehydrogenase (LDH) are biomarkers of healthy tissues, especially the liver or hepatopancreas. Therefore, any changes in these levels in the blood or hemolymph suggest tissue damage [70]. Moreover, changes in the lipid profile, total protein, albumin, globulin, glucose, and other analytes in the blood indicate occurrences in the liver, kidney, and gill tissues in aquatic animals exposed to different xenobiotics. Similar changes in blood biochemical parameters were reported in
4.4 Physiological biomarkers
Physiological biomarkers indicate changes in organ function, hormone levels, immune responses, osmoregulation, and other physiological processes that may be affected by pollutants.
In this section, we present some examples of physiological changes reported in different species of aquatic animals exposed to xenobiotics Changes in the various physiological aspects of aquatic animals can assist toxicologists in assessing the toxicity of xenobiotics. For example, exposure to chlorpyrifos significantly affects sex hormone biosynthesis in the gonads of
Katuli et al. showed that diazinon can affect the osmoregulation mechanism in Caspian roach (
4.5 Histological biomarkers
In histopathology, tissue structure, cellular morphology, inflammation, and any histopathological changes are studied in finfish and shellfish exposed to pollutants. Xenobiotics and their metabolites can induce histopathological damage in vital organs. Therefore, histological studies as biomarkers can help scientists assess the extent of injury in various tissues [94]. Damage to cells, necrosis of tissues, and histopathological damage were observed in the vital organs of aquatic animals exposed to different pollutants [57, 95]. Therefore, histopathological biomarkers are also used as cellular biomarkers in certain situations [96]. Exposure to pesticides can induce histopathological damage to vital tissues of aquatic animals [97, 98]. For example, histopathological changes were reported in the gills, liver, spleen, and kidney of
4.6 Genetic biomarkers
Changes in DNA and RNA structure, gene expression, gene mutation rates, and epigenetic modifications are known as genetic biomarkers. The assessment of DNA adduct formation, micronucleus formation, and comet assay indicate DNA damage in finfish and shellfish exposed to xenobiotics. We mentioned that exposure to xenobiotics can induce cell signaling that controls the gene expression of enzymes involved in detoxification. Therefore, the analysis of gene expression of enzymes participating in detoxification can be used as genetic biomarkers for ecotoxicology. Guilherme et al. found that exposure to glyphosate induced DNA damage in
4.7 Behavioral biomarkers
Changes in the behavior of finfish and shellfish can be used as behavioral biomarkers. Studies have shown that exposure to certain xenobiotics may disrupt nervous system functions. Therefore, changes in the behavior of aquatic animals may be related to nervous dysfunction [121].
Changes in feeding behavior, grazing style, predator evasion, prey pursuit, swimming patterns, courtship behaviors, nesting, parental care, territoriality, etc., are important indicators for behavior monitoring. Shiry et al. found that exposure to diazinon led to changes in the behavior and physiology of freshwater swan mussels (Figure 5) [122].
Figure 5.
Behavioral biomarkers.
Behavioral changes were observed in goldfish [123], rainbow trout [124], and zebrafish exposed to different pollutants [125].
4.8 Biomarkers of microbial community structure
Exposure to different xenobiotics can affect the microflora of the intestine and skin of aquatic organisms. Changes in the variety and frequency of certain microorganisms in the microbiome may impact growth performance, immune response, and overall health of fish and shellfish [126]. Therefore, studying the microbial community of the intestine of aquatic organisms is a suitable biomarker for monitoring the toxicity of xenobiotics. Exposure to pentachlorophenol significantly changed the gut microbial community of
4.9 Ecological biomarkers
Exposure to xenobiotics may cause the death of some aquatic organisms within the food web, which can subsequently affect other animals living in the polluted ecosystem [27, 54, 131]. Furthermore, environmental pollutants can affect both biological and non-biological components of water ecosystems. As a consequence, the aquatic ecosystem may attempt to establish a new ecological balance. Therefore, changes in the biological and non-biological components of the ecosystem can be used as ecological biomarkers. Moreover, alterations in the responses of aquatic organisms to ecological changes, such as migration from polluted sites, physiological responses, behavioral changes, may also serve as indicators [122]. Ramya et al. showed that changes in osmoregulation mechanisms in
5. Conclusion
Analytical chemical analysis combined with properly chosen biological endpoints assessed in the tissues of species of concern can help ensure the health of aquatic ecosystems and identify species in danger from the harmful impacts of environmental contaminants. These biological endpoints include the biomarkers that, when combined, allow for a better understanding of the effects of non-chemical stressors while shedding light on questions like contaminant bioavailability, bioaccumulation, and ecological repercussions. Although biomarkers are not a novel concept, their application in ecological risk assessment and natural resource damage assessment has been lacking. These methods can aid in a more thorough evaluation of the intricate consequences of coastal development activities and ecological integrity from a regulatory perspective. In situations where complex mixes of pollutants are prevalent, the use of the mono-biomarker approach is not enough for the assessment of various biological responses that indicate the quality of the environment and for the detection of exposure to contaminants present at low levels in the environment. These pollutants can in fact evolve into irreversible alterations and bring permanent damage to natural populations that are integral parts of aquatic ecosystems. For this reason, researchers contribute to the development of a multi-biomarker approach, able to investigate the different toxicological responses in aquatic organisms, which represents a fundamental tool for more accurate environmental monitoring of the population and the potential danger deriving from contamination [133]. It is necessary to evaluate the clinical risk associated with the detected hazard, which is contingent upon several parameters, such as patient health, metabolic stability, pharmacodynamic response, exposure, and indication. While identifying hazards is comparatively simple, assessing risks is a complex and demanding process.
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