Oxidative stress as a possible mechanism of toxicity of the herbicide 2,4-Dichlorophenoxyacetic Acid (2,4-D)

BETTINA BONGIOVANNI; CINTIA KONJUH; ARÍSTIDES POCHETTINO; ALEJANDRO FERRI

Herbicides - Properties, Synthesis and Control of Weeds

InTech

Lugar: Rijeka; Año: 2012; p. 315 - 334

Chlorophenoxy herbicides are widely used in agriculture and forestry, for the control of broad-leaved weeds in pastures, cereal crops, and aside the roads. Structurally, these compounds consist of a simple aliphatic carboxylic acid moiety attached to a chlorine-substituted aromatic ring via an ether linkage. One of the most commonly used herbicides of this class is 2,4-dichlorophenoxyacetic acid (2,4-D), which is known to disrupt the mechanisms of biological responses to hormones in plants. 2,4-D was synthesized and offered for the first time in the U.S. market in 1940 and has been produced worldwide since 1950. After 2,4-D use as a domestic herbicide and as a component of Orange Agent was intensely widespread, the study of its toxicity deserved an increasing interest. Human exposure to chlorophenoxy herbicides may occur through inhalation, skin contact, or ingestion. The predominant route of occupational exposure has been the absorption of spills or aerosol droplets through the skin. Moreover, in developing countries, rural population can be affected by severe nutritional deficiencies, some of which could increase its vulnerability to environmental pollutants, especially during the critical period of development. Some rat studies of our laboratory has shown that different doses of 2,4-D (50, 70 or 100 mg/kg bw/day) produce a wide range of adverse effects, from embryotoxicity to neurotoxicity. 2,4-D acid can pass from mothers to suckling pups, through the breast milk, inhibiting the suckling-induced hormone release in lactating rats. Thus, gestational and lactational periods, as well as the neonatal and prepubertal stages, seem to be particularly favorable for the induction of 2,4-D effects in rodents. Herbicide exposure (through dam´s milk) alters the tissue contents of Fe, Cu and Zn. As long as metal ions are known to be associated with the status of many Reactive Oxygen Species, these agents could affect the tissue oxidative status. Herbicides are also known to affect the monoamine transmitter in the pup brain. A decrease in dopamine content in the prefrontal cortex has been associated to the induction of dopamine oxidation through a stimulation of ROS production. Moreover, 2,4-D reduces norepinephrine and DOPAC contents in the striatum, affecting the oxidative state through an increase in ROS levels and a decreased activity of some protecting factors as glutahione (GSH), catalase (CAT) and GSH peroxidase (GPx). On the other hand, the 2,4-D exposure through the dam´s milk increases tissue ROS level, lipid peroxidation and protein oxidation in rat ventral prostate at different stages of development. In addition, 2,4-D acid induces an oxidative imbalance in the breast, mainly during puberty and adulthood, and affects antioxidant enzymes distinctly in the rat ovary at different ages. Recently, the oxidative stress has been pointed out as a cause of disturbances of human infertility. Some studies have shown 2,4-D toxic effects in vitro in cell cultures. Both morphological and biochemical alterations have been associated to specific 2.4-D toxic effects on rat cerebellar granule cells (CGC). The herbicide produces cellular death in CGC in culture at 1 and 2 mM, possibly affecting some common, early events in either or both, cell necrosis or apoptosis. However, some reported mitochondrial disorders could be irreversibly compromised in neuron necrosis, but not so in apoptosis. Although 2,4-D is known to alter the oxidative parameters affecting selectively some enzymatic activities and to increase the ROS level in CGC in culture, the collected evidence suggests that 2,4-D induced apoptosis could be mediated by or associated to an oxidative imbalance at the cellular level. These results would suggest that 2,4-D acid is an environmental pollutant that induces oxidative stress and could adversely affect the development of both neural and reproductive systems. As far as rat development during the neonatal period (early lactation) is comparable to the last two trimesters of human gestation, the reported studies point out the need of a further evaluation of 2,4-D effects in utero and during lactation in human studies. Importantly, the effects of herbicide exposure seem to be highly subjected to the interaction of the developmental period and nutritional status of the studied individual.