Maternal Exposure to Acephate Caused Nephrotoxicity in Adult Offspring Rats Mediated by Excessive Autophagy Activation, Oxidative Stress Induction, and Altered Epithelial Sodium Channel and Na(+)/K(+)-ATPase Gene Expression

SIMPLE SUMMARY: Although continuous exposure to conventional pesticides has been linked to tissue dysfunction among humans and animals, there is little information regarding the environmental disturbances and their harmful effects on fetuses. In the present study, we investigated the anomalies caused by oral acephate exposure on the kidney function in rat offspring in utero. Moreover, this harmful organic pollutant has been reported to promote the development of various cell injuries and tissue functional disorders, such as reproductive toxicity and diabetes. In addition, we found that exposure to acephate during pregnancy can alter renal integrity and induce nephrotoxicity in rat offspring. Furthermore, acephate exposure aggravated kidney injury by enhancing oxidative stress, autophagy, apoptosis, and histopathological alterations. As humans experience increased exposure to agrochemicals worldwide, the obtained data will advance the knowledge of how an unfavorable fetal environment can affect the offspring’s health during adulthood. ABSTRACT: This study examined how maternal exposure to acephate—an organophosphate-based insecticide—affected the renal development in rat offspring during adulthood. Virgin female Wistar rats were randomly allocated to three groups: group 1 (control) received sterile water; groups 2 and 3 were intragastrically exposed to low (14 mg/kg) and high (28 mg/kg) doses of acephate from day 6 of pregnancy until delivery, respectively. Further, the offspring of the adult female rats were euthanized in postnatal week 8. Compared with the controls, the adult rat offspring with exposure to low and high doses of acephate exhibited elevated plasma creatinine and blood urea nitrogen levels. Additionally, immunofluorescence analysis revealed the upregulation of autophagic marker genes (Beclin-1 and LC-3) in the acephate-treated rat offspring, thereby suggesting the induction of an autophagic mechanism. Notably, the increased malondialdehyde level, decreased glutathione level, and decreased superoxide dismutase and catalase activities confirmed the ability of acephate to induce oxidative stress and apoptosis in the kidneys of the rat offspring. This may explain the renal histopathological injury detected using hematoxylin and eosin staining. Furthermore, a reverse transcription polymerase chain reaction revealed that the mRNA expression levels of the Na(+)/K(+)-ATPase and the epithelial sodium channel (ENaC) genes were significantly higher in the kidney of female offspring than that of controls owing to acephate toxicity. However, there was no significant effect of acephate on the expression of NHE3 in the treatment group compared with the control group. Overall, the present findings suggest that oxidative stress caused by prenatal exposure to acephate causes nephrotoxicity and histopathological alterations in adult rat offspring, likely by actions on renal ENaC and Na(+)/K(+)-ATPase genes as well as the autophagic markers Beclin-1 and LC-3.