Seventh research Naringenin alleviates roundup-induced cytoarchitectural derangement of rat hypothalamic-pituitary-adrenal axis via modulating Sirt1/NF-κB/Nrf2 and p38-MAPK/p53 signaling pathways ABSTRACT Background: Roundup is one of the most widely used herbicides in the world. It has potential endocrine disruption and neurotoxic effects. Naringenin (NG) is a flavonoid that has a neuroendocrinal protective ability. Aim: To identify the cytoarchitectural alterations that may happen in the rat hypothalamicpituitary-adrenal axis following Roundup exposure, and to evaluate the potential alleviating effect of NG. Material and methods: Forty male Sprague Dawley rats were randomly allocated into four equal groups (n = 10 per group): Control group, NG group was administered naringenin at a dose of 50 mg/ kg BW, Roundup group was received 244 µl/kg BW of Roundup, and Roundup + NG group was administered 244 µl/kg BW/day of Roundup along with 50 mg/ kg BW of NG. All groups except the control group were treated orally every day for 14 days. Biochemical, molecular, histopathological and immunohistochemical evaluation of the paraventricular nucleus of hypothalamus, anterior pituitary, and adrenal glands were conducted. Results: Roundup group revealed a hormonal imbalance, increased levels of inflammatory biomarkers and malondialdehyde, while a decline in the antioxidant enzyme activities. There was an upregulation of p38-MAPK in both adrenal and pituitary glands, accompanied by downregulation of Cyp11a1 and Sirt1 in the adrenal and pituitary glands, respectively. Cytoarchitectural alterations and an increase in the immunoexpression of Nrf2 and p53 were detected in Roundup group. Co-administration of NG resulted in marked improvement. Conclusions: Roundup provokes oxidative damage, inflammation along with hormonal, molecular, and structural alterations in the hypothalamic-pituitary-adrenal axis. Cotreatment with naringenin has mitigated these adverse effects.