Rifaximin Protects against Malathion-Induced Rat Testicular Toxicity: A Possible Clue on Modulating Gut Microbiome and Inhibition of Oxidative Stress by Mitophagy

Abstract

Testicular dysfunction is caused by chronic exposure to environmental pollution, such as malathion, which causes oxidative stress, promoting cell damage. Autophagy is a key cellular process for eliminating malfunctioning organelles, such as the mitochondria (mitophagy), an eminent source of reactive oxygen species (ROS). Autophagy is crucial for protection against testicular damage. Rifaximin (RFX) is a non-absorbable antibiotic that can reshape the gut microbiome, making it effective in different gastrointestinal disorders. Interestingly, the gut microbiome produces short chain fatty acids (SCFAs) in the circulation, which act as signal molecules to regulate the autophagy. In this study, we investigated the regulatory effects of RFX on gut microbiota and its circulating metabolites SCFA and linked them with the autophagy in testicular tissues in response to malathion administration. Moreover, we divided the groups of rats that used malathion and RFX into a two-week group to investigate the mitophagy process and a four-week group to study mitochondriogenesis. The current study revealed that after two weeks of cotreatment with RFX, apoptosis was inhibited, oxidative stress was improved, and autophagy was induced. More specifically, PINK1 was overexpressed, identifying mitophagy activation. After four weeks of cotreatment with RFX, there was an increase in acetate and propionate-producing microflora, as well as the circulating levels of SCFAs. In accordance with this, the expression of PGC-1α, a downstream to SCFAs action on their receptors, was activated. PGC-1α is an upstream activator of mitophagy and mitochondriogenesis. In this sense, the protein expression of TFAM, which regulates the mitochondrial genome, was upregulated along with a significant decrease in apoptosis and oxidative stress. Conclusion: we found that RFX has a positive regulatory effect on mitophagy and mitochondria biogenesis, which could explain the novel role played by RFX in preventing the adverse effects of malathion on testicular tissue.

Effect of Long-Time Malathion Administration on Testosterone, Oxidative Stress, and Sperm Characteristics in Rats

“…that had the highest levels of lipid peroxidation and the lowest concentrations of both GSH and GPx. (Omar et al, 2022b) have reported that malathion exposure significantly reduced sperm count and motility as well as serum testosterone levels when using three different concentrations (25 mg/kg, 50 mg/kg, and 100 mg/kg) when using it for two and four weeks, which is consistent with the findings of our study at a dose of 27 mg/kg (3 times/week) for 60 days of exposure to malathion.…”

“…Malathion is an organophosphorus (OP) insecticide that has been shown to disrupt sperm quality and impair reproductive hormone synthesis by inducing a cascade of oxidative stress (Omar et al, 2022b). (Massoud, 2022) suggested that malathion affects the germinal and somatic cells of the testis and lowers testosterone activity, which inhibits spermatogenesis by causing Sertoli cells and germ cells to become damaged and vacuolated.…”

“…The indiscriminate and excessive use of pesticides, especially the common ones in Egypt such as malathion in the developing villages, causes many problems that directly negatively affect human health and indirectly through animal byproducts that humans feed on, even those that are frozen for long periods (Hassouba, M. et al, 2007). Even at low dosages, persistent malathion exposure is frequently associated with severe hepatic, renal, and testes problems in laboratory animals (Badr, 2020;Omar et al, 2022a), due to it has been demonstrated that malathion intoxication increases oxidative stress as a result of excessive production of reactive oxygen species (ROS) and exhaustion of the body's natural antioxidant defense system, which interact with biomolecules to cause lipid peroxidation, numerous biochemical inactivation, and DNA damage (Ibrahim et al, 2020). (EL ASUOTY, M.S et al, 2017) reported that farm animals eating feed and grains exposed to malathion can transfer it to milk and its derivatives.…”

Tactics with Prebiotics for the Treatment of Metabolic Dysfunction-Associated Fatty Liver Disease via the Improvement of Mitophagy

“…The mitochondria dysfunctions suppress the β-oxidation of mitochondria and increase the production of the toxic lipid metabolism, which further adversely affects the mitochondrial dysfunction [ 102 ]. Interestingly, the gut microbiota could produce short-chain fatty acids (SCFAs), which might act as signal molecules to regulate the autophagy [ 103 , 104 ]. Therefore, the modulation of microbiota has been shown to control the machinery of autophagy against liver toxicity [ 105 ].…”

The Molecular Gut-Brain Axis in Early Brain Development

“…It is assumed that microbiota modify DNA methylation in a genome-specific or non-genome-specific manner. For instance, the microbiota can induce oxidative stress by generating mitochondrial reactive oxygen species (ROS) via autophagy [ 89 ]. Oxidative stress modulates DNA methylation, thereby changing gene expression.…”