**4. Pesticides and endocrine disruption**

enzymatic and nonenzymatic antioxidant mechanisms to protect cellular components from

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

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].

oxidative damage [79].

210 Toxicology Studies - Cells, Drugs and Environment

antioxidants [83].

The endocrine system refers to glands located in several areas of the body. Glands release some hormones that enter the circulation and act on specific "target" organs. If an event disrupts the endocrine system, some organs will not receive the correct amount of hormones and might not function properly or even function wrongly. In this context, low levels of some pesticides in the environment can impair the endocrine system [85].

Besides their primary action as pesticides, organophosphorus, carbamates, and organochlor‐ ines can act as endocrine disruptors and affect the function of hormones by blocking, mim‐ icking, displacing, or acting to subvert their natural roles in living species. DDT and its metabolites are among the most famous endocrine disruptors. DDT was widely used in the 1950s and 1960s, and it is still allowed in some countries. Its proven estrogenic action can affect the reproductive system of mammals and birds [86].

In vitro and in vivo studies have shown that pyretroids also act as endocrine disruptors, but their effects only arise at relatively high levels [87]. Atrazine, a triazine herbicide, may also exert endocrine-disrupting effects on amphibians [5].
