**3. Pesticides and oxidative stress**

**Physical and Chemical**

**Exposition**

**Toxicokinetics** peroxidation and cell

injury37.

Marketed primarily as the

isopropylamine salt (glyphosate)

Formation of

Seizures, respiratory

208 Toxicology Studies - Cells, Drugs and Environment

arrest, coma, and

disturbance of

Maintenance of the vital

consciousness and

functions54.

irritation upon local

contact33.

aminomethylphosphon

DNA damage and

uncoupling the electron

transport chain 49,50.

ic acid (AMPA) by

or ammonium salt (glufosinate).

Although compounds contain a

Skin,

gastrointestinal36.

action of

glyphosate

oxidoreductase36.

P=O moiety they do not inhibit

AChE such as

organophosphates36. Glyphosate

is a relatively strong acid with a

pH of 2 in 1% aqueous solution 21.

Maneb and Zineb, for example,

are identical in structure with

exception the cátion. Maneb is

They show slow

Biotransformation of

Your metabolic induces

thyroid cancer, modifies

Carcinogenic and

teratogenic action and

There is no specific treatment

for poisoning 55.

thyroid problems 55.

thyroid hormones and can

inhibit acetaldehyde

dehydrogenase 55.

dithiocarbamates form

ethylenethiourea (ETU)

absorption by oral

and dermal contact

moderately water soluble and

stable under normal conditions,

while Zineb are slightly soluble

16.

55.

in water and unstable in

light 21.

**Table 1.** Summary of the physicochemical properties and phase of the intoxication of different classes of pesticides

**Dithiocarbamates**

**Toxicodynamics**

**Signs and Symptoms**

kidney tubules, liver, and

replacement 41, 42.

lung38, 41.

**Treatment**

**Properties**

**Glycine**

**Derivatives**

Interest in the toxicological aspects of oxidative stress has grown in recent years. Many researchers have focused on the mechanistic aspect of oxidative damage and cellular responses in biological systems, mainly in the case of pesticides, because oxidative stress is a condition that stems from exposure to various classes of these compounds.

Oxidative stress occurs when the rate of reactive species production exceeds the rate of reactive species decomposition in antioxidant systems, which culminates in increased oxidative damage in different cellular targets [72]. Reactive species comprise substances that do not necessarily have unpaired electrons but are very reactive due to their instability [73]. Free radicals are atoms, molecules, or ions with unpaired electrons on an otherwise open shell configuration are examples of reactive species. Their electrons are usually highly reactive [74].

Oxygen and nitrogen free radicals play an essential role in the physiological control of cell function in biological systems. Living cells continuously produce these radicals [73]. In aerobic organisms, several basic cellular metabolic processes induce production of reactive oxygen species (ROS) within cells. Cellular respiration involves reduction of molecular oxygen (O2) to water during oxidative phosphorylation in the electron transport chain, to generate reactive, partially reduced intermediates such as the superoxide anion radical (. O2- ), hydrogen peroxide (H2O2), and the hydroxyl radical (HO. ) [75]. Around 5% of these ROS originate from electron transport chain processes and can damage cellular components [76]. Moreover, several enzymes produce ROS, thereby constituting a second source of ROS synthesis in cells [77].

Regulated ROS production is higher in organisms, and maintenance of redox homeostasis is essential for the physiological health [78]. Living organisms have developed adequate enzymatic and nonenzymatic antioxidant mechanisms to protect cellular components from oxidative damage [79].

Exposure to some xenobiotics, especially toxic chemical pollutants, such as pesticides, may produce an imbalance between endogenous antioxidants and ROS, with subsequent decrease in antioxidant defenses to trigger oxidative stress in biological systems, damage to tissues, inflammation, degenerative diseases, and aging [79]. As mentioned previously, many classes of pesticides induce oxidative stress, through several different mechanisms. They may affect the redox cycle by donating electrons to or withdrawing electrons from cell components. During metabolism, they may deplete glutathione (endogenous antioxidant) or even inactivate other endogenous antioxidants [74]. In short, oxidative stress can take place either through overproduction of free radicals or alteration in antioxidant mechanisms [80]. Increased concentration of plasma and red blood cell thiobarbituric acid reactive substances (TBARs), changes in the antioxidant status, and altered activities of cellular enzymes such as superoxide dismutase (SOD) and catalase (CAT) indicated higher oxidative stress in pesticides sprayers. Hence, many researchers have associated exposure to pesticides with oxidative stress [81].

Several works have described oxidative stress induction after exposure to organophosphorus insecticides. The stress is a result of intracellular Ca+2 influx, which leads to cholinergic hyperactivity and activates proteolytic enzymes and nitric oxide synthase, which in turn generates free radicals [74]. Fenitrothion, a phosphorothioate, has been linked to histopatho‐ logical effects on the liver and kidneys and cytotoxic effects on the lungs. These effects originate from ROS generation via pesticide metabolism by P450 or via high-energy consumption coupled with inhibition of oxidative phosphorylation [82]. Moreover, hydrocarbon insecti‐ cides chlorinated like DDT can induce oxidative stress after metabolic activation by CYP450 [80].

Synthetic pyrethroids are less persistent and less toxic to mammals and birds. Deltamethrin is one of the pyrethroids that has found wide acceptability. Nevertheless, this pyrethroid has effects on the nervous, respiratory, and hematological systems in fish, and it displays tumor‐ igenicity in rodents [80]. All these effects are due to oxidative stress; they impact various antioxidants [83].

A classic example of oxidative stress induction among pesticides is the action of dipyridyls such as paraquat. This compound enters the redox cycle and constantly generates ROS such as the superoxide anion and the hydroxyl and peroxyl radicals [74]. ROS play a crucial role in the development of paraquat-induced pulmonary injury [38]. The basic mechanism of oxidative stress in this class is simple: the dipyridyl initiates a cyclic oxidation/reduction process. First, they undergo one-electron reduction by NADPH to form free radicals. The latter donate their electron to O2, to give a superoxide radical. Upon NADPH exhaustion, to superoxides react to produce hydroxyl free radicals and other reactive species that lead to oxidative stress and consequent cell death [80]. The free radicals react with lipids in cell membranes, to start a destructive process known as lipid peroxidation. The lung is the organ that is mostly involved in this case [38]. Other compounds, like dithiocarbamates mainly inhibit antioxidant enzymes, such as SOD and catalase [84].

Pesticides can induce free radical formation by altering the way that cell organelles, like mitochondria operate. Rotenone, an insecticide of the class of rotenoids, strengthens the case for complex I inhibition – rotenone specifically binds to complex I, to inhibit the electron flow through the respiratory chain. Deficiencies in the mitochondrial respiratory chain diminish ATP synthesis and produce ROS, which culminates in oxidative stress, mitochondrial depo‐ larization, and initiation of cell death processes [16, 75].

In this context, many studies in human or animals have evidenced that pesticides exert their toxic action in the body via oxidative stress induction both upon acute and chronic exposure.
