**6. Mitochondrial membrane structures and dynamics in pyrethroid intoxication**

Another effect of pyrethroids is on the structural integrity and dynamics of mitochondria observed in histopathological studies. *cis*-Permethrin has caused inner membrane disruption, and the cristae have been replaced with a denser matrix in Leydig cells of mice testis [137]. Therefore, hitching of cholesterol delivery diminished the pregnenolone formation, contributing to the endocrine disrupting function of pyrethroids. Mitochondrial swelling associated with ER cisternae has been observed in the liver of cypermethrin exposed rats [138]. Dilated round or ovoid mitochondria with short cristae and clear matrix have also been noticed while small damaged mitochondria containing electron dense inclusions occurred in different time series. A similar result has also been found from an amphibian study. According to Yilmaz et al. [139], severely damaged cristae and loss of mitochondrial matrix have been found in the cypermethrin exposed sciatic nerves of *Rana ridibunda*. Typical tubular appearance loss, perturbed fusion/fission equilibrium favoring the fission, and decreased mitochondrial membrane potential have been observed in tefluthrin, deltamethrin, bifenthrin, and α-cypermethrin exposed rat cerebral astrocytoma C6 cells with an increase in cell death ratio [140]. Obvious mitochondrial hypertrophy with distended membranes has been found in the liver of deltamethrin exposed rats [92]. Deltamethrin exposure resulted in irregular contours of mitochondria, tiny and few cristae, and cloudy matrix. Mitochondrial morphometry has also been affected by deltamethrin exposure. Therefore, mitochondria may be the most vulnerable organelle with its structure-function relationship for pyrethroids toxicity.

Pyrethroids can pass and interact with biological membranes because of their lipophilic nature [84]. As mitochondrion stand its membranous structures, mitochondrial membranes and other proteins in addition to the electron transport proteins are candidate structures for pyrethroid action. For example, fenvalerate has not interacted with mitochondrial membrane proteins measured with intrinsic protein fluorescence, mainly by tryptophan fluorescence quenching in the isolated mitochondria from *Helicoverpa armigera* larvae (cotton bollworm) [141]. Because of its hydrophobic nature, deltamethrin has increased the mitochondrial membrane rigidity in the isolated rat liver mitochondrial preparation and this can cause the impaired transport of different ions between cytosol and mitochondrial matrix [90]. Permethrin has caused a decrease in mitochondrial membrane fluidity and this could be a reason for a bioenergetic crisis in the cell because of irregular energy transduction in striatum submitochondrial particles of rats [88]. Mitochondrial membrane fluidity at the hydrophilichydrophobic region of the bilayer has decreased, while fluidity in the hydrophobic core increased in the heart of 300-day old rats exposed the permethrin between 6 and 21 days of their life [142]. Moreover, decreased cholesterol levels in mitochondrial membranes have been observed while it increased in the plasma membrane of heart cells. Therefore, these observations and pro-oxidative properties of permethrin could cause the altered cardiac ultrastructure and function. This effect of permethrin has also been found in Leydig cells of mice testis as discussed above [137]. As an integral membrane protein, VDAC interacts with membrane cholesterol [143] and ATP synthesis, ATP/ADP exchange by adenine nucleotide translocator (ANT) at the inner membrane, ATP/ADP and metabolite exchange by VDAC can be affected by associated membrane composition [93].

Therefore, pyrethroids can be effective on cells at different levels of metabolism. In a similar manner, permethrin caused a significant elevation of *pdk4* and *phosphoenolpyruvate carboxylase (pepck)* gene transcripts in the muscle and liver of mice, respectively [132]. Permethrin exposure displayed similar results [133] that were seen in the study of Kim et al. [128]. In addition, phosphorylated Akt at Thr308 and glucose transporter 4 (glut4) protein levels have been decreased in the muscle; therefore, authors concluded that permethrin can alter the glucose and lipid metabolism via an AMPK-dependent pathway and produce insulin resistance and obesity risk in exposed groups. In contrast, insulin-stimulated Akt phosphorylation has been decreased by permethrin in pAMPK-independent and the ERK-dependent manner in C2C12 myotubes, and this mechanism could be a reason for insulin resistance development [134]. Therefore, the exact mechanism of lipid accumulation in different cell types may use different pathways; however, we believed that ER-mitochondria axis and their relation in Ca2+ and ROS

Affected lipid metabolism by pyrethroids has also been observed in other studies including

Another effect of pyrethroids is on the structural integrity and dynamics of mitochondria observed in histopathological studies. *cis*-Permethrin has caused inner membrane disruption, and the cristae have been replaced with a denser matrix in Leydig cells of mice testis [137]. Therefore, hitching of cholesterol delivery diminished the pregnenolone formation, contributing to the endocrine disrupting function of pyrethroids. Mitochondrial swelling associated with ER cisternae has been observed in the liver of cypermethrin exposed rats [138]. Dilated round or ovoid mitochondria with short cristae and clear matrix have also been noticed while small damaged mitochondria containing electron dense inclusions occurred in different time series. A similar result has also been found from an amphibian study. According to Yilmaz et al. [139], severely damaged cristae and loss of mitochondrial matrix have been found in the cypermethrin exposed sciatic nerves of *Rana ridibunda*. Typical tubular appearance loss, perturbed fusion/fission equilibrium favoring the fission, and decreased mitochondrial membrane potential have been observed in tefluthrin, deltamethrin, bifenthrin, and α-cypermethrin exposed rat cerebral astrocytoma C6 cells with an increase in cell death ratio [140]. Obvious mitochondrial hypertrophy with distended membranes has been found in the liver of deltamethrin exposed rats [92]. Deltamethrin exposure resulted in irregular contours of mitochondria, tiny and few cristae, and cloudy matrix. Mitochondrial morphometry has also been affected by deltamethrin exposure. Therefore, mitochondria may be the most vul-

**6. Mitochondrial membrane structures and dynamics in pyrethroid** 

nerable organelle with its structure-function relationship for pyrethroids toxicity.

Pyrethroids can pass and interact with biological membranes because of their lipophilic nature [84]. As mitochondrion stand its membranous structures, mitochondrial membranes and other proteins in addition to the electron transport proteins are candidate structures for

signaling are the main curators of these effects of pyrethroids.

fish and mammals [135, 136].

**intoxication**

306 Mitochondrial Diseases

Effects of pyrethroids are not limited to mitochondrial membranes because of fluidity decline in the hydrophobic core of cypermethrin exposed rat erythrocyte plasma membrane [144]. Similar fluidity decline has been observed in deltamethrin exposed common carp (*Cyprinus carpio*) erythrocyte plasma membranes [145]. Phosphatidylethanolamine, phosphoglyceride, phosphatidic acids, and cardiolipin levels were decreased, making the membrane more rigid and less permeable. Decreasing these components can cause oxidative stress and cell membrane ageing. Interestingly, cardiolipin is an exclusive component of the inner mitochondrial membrane, and it plays a significant role in governing the mitochondrial bioenergetics processes (interaction with respiratory chain proteins and substrate carriers) and dynamics [146]. Cardiolipin reduction has been observed via ROS-induced lipid peroxidation in nerve growth factor-deprived rat sympathetic neurons and this has caused the loss of mitochondrial density [147]. As a membranous structure, the same finding may be observed with mitochondrial preparations, but it is an issue for further studies. It has been concluded that high lipophilicity and pro-oxidative potential of pyrethroids can affect the biological membranes with their functional proteins to mediate the dysfunctional mitochondria.

While 18 kDa translocator protein (TSPO; formerly known as peripheral benzodiazepine receptor) ligands PK 11195 and Ro5-4864 are anti-apoptotic in the concentrations close to their TSPO affinity, they can also be pro-apoptotic agents at higher levels [148, 149]. It has been evidenced that pyrethroids can bind and interact with TSPO [150, 151], located on the mitochondrial outer membrane and participates to cholesterol transport as a cholesterol channel into mitochondria collectively with VDAC and ANT [152, 153]. Many type I and type II pyrethroids can bind this protein on rat brain membranes, while fluvalinate and fenvalerate have poor potency [154]. Furthermore, *cis*-permethrin has decreased the mRNA levels of *tspo* in mice testis [137]. In the study of Vadhana et al. [142], mitochondrial cholesterol levels have been decreased, while cellular and plasma cholesterol levels increased in the heart of permethrin exposed rats. The pyrethroids may interact with TSPO protein with high affinity to affect its interaction with VDAC [93] to decrease cholesterol levels in mitochondria. Because mitochondrial function mostly depends on its membranous structures, a decrease in membranous and inner mitochondrial cholesterol levels could be effective on ROS production and abnormal autophagy as is exemplified above sections. Increased TSPO to VDAC ratio has been correlated with increased ROS production, decreased mitophagy, and accumulation of damaged mitochondria [155, 156]. Therefore, oxidative-stress inducing and apoptotic potential of pyrethroids could also be originated with this capability. TSPO attends to the ROS formation via mitochondrial membrane potential transition [148]. Produced ROS affect the bonding form of cytochrome c to cardiolipin through the tightly to loosely conformation and results in the release of it [157] to induce mitochondrial apoptotic pathway. Interestingly, in the events of VDAC closure and blockage of TSPO function cause a permeability increase of VDAC to Ca2+ and this can accelerate the mtPTP opening [158].

We believed that pyrethroids can interact with mtDNA as seen in their electron transport complex bonding potential; therefore, can create mutations on mtDNA. However, further

Pyrethroid Insecticides as the Mitochondrial Dysfunction Inducers

http://dx.doi.org/10.5772/intechopen.80283

309

In conclusion, pyrethroids can perform their toxic action via their oxidative potentials including unbalanced Ca2+ flux in/out of the organelles and cells. Mitochondria might be the most vulnerable organelle for pyrethroid toxicity. Pyrethroids probably can change the interaction of mitochondrion and ER to create an imbalance between the fine equilibrium of ROS and Ca2+ signals. This affects the form of cellular metabolic energy production, accumulation of lipids and other metabolites, and cell death type. Pyrethroids can also change the mitochondrial membrane structures to affect their ability for metabolism and ROS production capacity. These effects may be related to the endocrine disruption, diabetic, dopaminergic, and obesity-induction potential of pyrethroids that are observed in exposed individuals as exemplified in the above sections such as altered lipid metabolism and cholesterol delivery into the mitochondria. However, there are many gaps that must be solved, such as, interaction with mitochondrial membrane proteins, specific mutagenesis caused by pyrethroid molecule and mtDNA interaction, etc.

and Eylem Taskin3

1 Department of Biophysics, Faculty of Medicine, Nigde Omer Halisdemir University,

3 Department of Physiology, Faculty of Medicine, Nigde Omer Halisdemir University,

2 Department of Biology, Faculty of Science and Letters, Adiyaman University, Adiyaman,

[1] Oberemok VV, Laikova KV, Gninenko YI, Zaitsev AS, Nyadar PM, Adeyemi TA. A short history of insecticides. Journal of Plant Protection Research. 2015;**55**(3):221-226. Available from: https://www.degruyter.com/view/j/jppr.2015.55.issue-3/jppr-2015-0033/

[2] Davies TGE, Field LM, Usherwood PNR, Williamson MS. DDT, pyrethrins, pyrethroids

and insect sodium channels. IUBMB Life. 2007;**59**(3):151-162

\*

mechanistic research is needed.

**8. Conclusion**

**Author details**

, Yusuf Sevgiler<sup>2</sup>

\*Address all correspondence to: eylemtaskin@yahoo.com

Celal Guven<sup>1</sup>

Nigde, Turkey

Nigde, Turkey

**References**

jppr-2015-0033.xml

Turkey
