Carbonic Anhydrase Sensitivity to Pesticides: History
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Carbonic anhydrase (CA) is a widespread metalloenzyme playing a pivotal role in several physiological processes. Many studies have demonstrated the in vitro and in vivo sensitivity of CA to several classes of pesticides in both humans and wildlife. The review is aimed to discuss the literature to date available in this field, providing a comprehensive view useful to foresee perspectives for the development of novel CA-based pesticide biomarkers. The analysis of the available data highlighted the ability of several pesticide molecules to interact directly with the enzyme in humans and wildlife and to inhibit CA activity in vitro and in vivo. The analysis disclosed key areas of further research and at the same time identified some perspectives for the development of novel CA-based sensitive biomarkers to pesticide exposure, suitable to be used in several fields from human biomonitoring in occupational and environmental medicine to environmental monitoring on non-target species.

  • carbonic anhydrase
  • pesticide
  • biomarker

Carbonic anhydrase, catalyzing the reversible hydration of CO2 to HCO3- and H+, is a widespread metalloenzyme with its eight genetically distinct families: α-CA expressed in animals and algae, β-CA in plants and prokaryotes, γ-CA in archaea, δ-CA, ζ-CA and θ-CA expressed in marine diatoms, η-CA in protozoa, ι-CA in diatoms and prokaryotes [1–3].

Due to the central role of bicarbonate, protons, and CO2 in several physiological processes, CA is of pivotal importance in a number of functions. In animals, it is crucial in respiratory gas exchange, acid-base regulation, fluid secretion, metabolism, calcification, bone resorption, signal transduction, and cellular defenses against oxidative stress [4,5].

The animal αCAs show an active site, conically shaped, with a zinc atom at the base coordinated by a water/hydroxide ion and three histidines (His94, His96, His119). During catalysis, first, the Zn2+ bound hydroxide exerts a nucleophilic attack on CO2 producing zinc-bound bicarbonate that, in turn, is displaced by a water molecule [6]. Then, the Zn2+ bound hydroxide is regenerated by the proton transfer from the zinc-bound water molecule to the bulk solvent facilitated by the His64 residue acting as a proton shuttle.

This catalytic process is sensitive to inhibition by several agents. In the last decades, the research on CA inhibition has experienced a great impulse resulting in the discovery and synthesis of a number of compounds useful for therapeutic purposes [7,8].

On the other hand, several chemicals relevant to environmental pollution have proven to inhibit the catalytic activity of carbonic anhydrase. Among these, a number of works have demonstrated the sensitivity of CA to pesticides both in humans and wildlife. However, a comprehensive view of this topic is lacking in the literature.

Pesticides are widely used in agriculture, public health control, domestic environment for the control of a large variety of pests, but at the same time, their broad use raises concern about the risks for human health and the environment.

Humans are exposed to pesticides through occupational or environmental exposure. Workers in the agricultural sectors or in pesticide production are the groups mainly exposed to these compounds. The general population is exposed to pesticides and their degradation products indirectly through water, air, food, and dust, generally resulting in a low-level and long term exposure [9]. Moreover, pesticide run-off from agricultural lands and the subsequent release into water bodies further increases the dispersion of pesticides in the environment and, in turn, increases the probability of exposure of nontarget organisms in wildlife [10].

Over the last years, a great number of epidemiological studies have found significant relationships between the exposure to pesticides (via inhalation, ingestion, dermal contact, or across the placenta) with cancer, neurodevelopmental alteration in children, allergies, decreased fertility, and birth defects [11] in humans. In parallel, a number of ecotoxicological studies have demonstrated a wide array of negative effects on nontarget organisms in wildlife [12].

Pesticides can produce adverse effects, with a variety of alterations at the molecular, cellular, or tissue level, that can be used as biomarkers of exposure/effects in occupational and environmental medicine as well as in environmental toxicology studies [13].

Pesticide biomarkers are defined as molecular and cellular alterations in the human body or in a nontarget organism in response to pesticide exposure and can be useful for monitoring the presence of a chemical in the body, for detecting biological responses or assessing adverse health effects following exposure. Biomarkers of exposure detect the exposure of an organism to a chemical or mixture of chemicals. They can provide evidence of the route, pathway, and even the source of exposure; moreover, they can be useful for assessing the extent of exposure, its variations over time and among different populations. They can be represented by the direct measurement of the chemical of interest or its metabolites in the body fluids or can consist in an endogenous response reflecting the interaction of the compound with a subcellular target, such as the genesis of DNA or protein adducts detectable in the blood [13–17]. On the other hand, biomarkers of effect provide an assessment of toxicological effects in the organism, such as measurable biochemical, physiological, or behavioral alterations that can be directly related to the risk of adverse health effects. Biomarkers of susceptibility are represented by intrinsic characteristics of an organism that confers greater susceptibility to the adverse effects of exposure to a specific chemical. Clear examples are represented by polymorphisms of relevant xenobiotic-metabolizing enzymes [13].

The risk assessment and prevention of pesticide exposure are complex processes in relation to several factors such as, for example, the variations in the time and concentration of exposure, differences in the chemical structure and toxicity of the different classes of pesticides, mixtures of chemicals used, climate variations in the areas where the chemicals are used [18]. Therefore, the development of novel pesticide biomarkers is a growing need for improving the risk assessment process.

This review aims to analyze and discuss the literature produced in recent years on the sensitivity of CA to a wide range of pesticides in order to foresee perspectives for the development of novel pesticide biomarkers suitable for human and environmental biomonitoring.

This entry is adapted from the peer-reviewed paper 10.3390/ijms21103562

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