Action of the chemical agent fipronil (active ingredient of acaricide Frontline®) on the liver of mice: An ultrastructural analysis

Abstract

Fipronil, active ingredient of the acaricide Frontiline®, is a phenyl-pyrazolic derivative, and its efficacy in the elimination of several plagues, even in low concentrations, has already been demonstrated; however, its effect on nontarget organisms has not been thoroughly explained. In this sense, the objective of this study was to evaluate the effects of different dosages of fipronil on the liver of mice in artificial conditions. Results showed that the animals exposed to fipronil present significant ultrastrucutural changes in hepatic cells with evident cellular and cytoplasm disorganization in hepatocytes characterized by an increase in the number of organelles, mainly mitochondria and rough endoplasmic reticulum, organelles that, in the case of the exposed animals, were probably responsible for the enzymes' synthesis that have the function of inactivating the toxic metabolites. A fat accumulation in the hepatocytes' cytoplasm (steatosis) was observed, in addition to extended vacuolated areas, mainly in regions next to the cell nucleus. Alterations observed in the nuclei of the hepatocytes pointed out cell death processes. Moreover, Kupffer cells increased in number (hyperplasia) suggesting an increase in the phagocytic activity of the liver in the exposed animals.

Fipronil induced oxidative stress involves alterations in SOD1 and catalase gene expression in male mice liver: Protection by vitamins E and C

“…Liver, being an important metabolically active organ, increase in its weight is indicative of toxic nature of fipronil. This finding is in agreement with Ferreira et al () who reported hypertrophy of liver in mice treated with fipronil and attributed it to the increase in the number of cytoplasmic organelles, mitochondria and rough endoplasmic reticulum (RER). The most plausible reason for enhanced number of RER was thought to be their involvement in the metabolism of fipronil thereby increasing its ability to synthesize more cytochrome P450 (CYP) isoforms (Ferreira et al, ).…”

“…This finding is in agreement with Ferreira et al () who reported hypertrophy of liver in mice treated with fipronil and attributed it to the increase in the number of cytoplasmic organelles, mitochondria and rough endoplasmic reticulum (RER). The most plausible reason for enhanced number of RER was thought to be their involvement in the metabolism of fipronil thereby increasing its ability to synthesize more cytochrome P450 (CYP) isoforms (Ferreira et al, ). Although concrete evidence of rise in CYP is not available in rodents/laboratory animals, but Das et al () have shown that fipronil exposure in primary human hepatocytes causes induction of CYP3A4 and CYP1A1 by increasing mRNA as well as protein expression.…”

“…Severe degenerative and vacuolar changes in the hepatocytes with focal areas of necrosis and infiltration of mononuclear cells in hepatocytes adequately explain the degree of damage caused by fipronil treatment. Similar to these histopathological alterations hepatic steatosis, cytoplasmic vacuolation, pyknotic nuclei, and Kupffer cell proliferation were reported in mice after 7 days of intraperitoneal fipronil administration (Ferreira et al, ; De Oliveira et al, ). The interesting fact to be considered here is that, purity of fipronil used in these studies was only 80%; whereas we used technical grade fipronil having >96% purity.…”

Comparative effects of fipronil and its metabolites sulfone and desulfinyl on the isolated rat liver mitochondria

“…A study by Silva (2008) evaluated the effects of prolonged exposure of rats to the insecticide; they observed swollen hepatocytes and increased liver weights in animals treated with an oral 10 mg kg −1 dose, which corresponds to one tenth of the LD 50 established for rat (Tingle et al, 2003). Additionally, mice livers examined following exposure to different fipronil doses (15, 25 and 50 mg kg −1 ) revealed cytological, morphological, and histochemical alterations in hepatocytes with autophagic processes, steatosis and necrotic cell death (Ferreira et al, 2012;Oliveira et al, 2012). Recent study using perfused rat liver showed that fipronil (10-50 M) interferes with energy metabolism causing hepatotoxicity, as demonstrated by the increase in the activity of lactate dehydrogenase in the effluent perfusate (Medeiros et al, 2015).…”

Citotoxicity of Fipronil on Hepatocytes Isolated from Rat and Effects of Its Biotransformation

“…Liver cells that were exposed to low concentrations of fipronil (0.1 mM), in addition to decreasing the ATP, experienced the activation of enzymes that participate in the process of apoptosis, i.e., caspase 3 and 7 (Das et al 2006). Histological studies also demonstrated the disorganized and modified cell nucleus of hepatocytes, with chromatin condensation and marginalization, indicating the occurrence of apoptosis (Ferreira et al 2012). During the biotransformation of xenobiotics in the liver, the generated metabolites may be more toxic than the parent compound (Ioannides and Lewis 2004).…”