Smart Hesperidin/Chitosan Nanogel Mitigates Apoptosis and Endoplasmic Reticulum Stress in Fluoride and Aluminum-Induced Testicular Injury

Nora S Deiab; Ahmad S Kodous; Mohamed K Mahfouz; Alshaimaa M Said; Mohamed Mohamady Ghobashy; Omayma A R Abozaid

doi:10.1007/s12011-023-03991-8

Smart Hesperidin/Chitosan Nanogel Mitigates Apoptosis and Endoplasmic Reticulum Stress in Fluoride and Aluminum-Induced Testicular Injury

Biol Trace Elem Res. 2023 Dec 13. doi: 10.1007/s12011-023-03991-8. Online ahead of print.

Authors

Nora S Deiab¹, Ahmad S Kodous^{2

3}, Mohamed K Mahfouz⁴, Alshaimaa M Said⁴, Mohamed Mohamady Ghobashy⁵, Omayma A R Abozaid⁴

Affiliations

¹ Biochemistry and Molecular Biology Department, Faculty of Veterinary Medicine, Benha University, Benha, Al Qalyubiyah, Egypt. Nora.Diab20@fvtm.bu.edu.eg.
² Radiation Biology Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt.
³ Department of Molecular Oncology, Cancer Institute (WIA), P.O. Box 600036, 38, Sardar Patel Road, Chennai, Tamilnadu, India.
⁴ Biochemistry and Molecular Biology Department, Faculty of Veterinary Medicine, Benha University, Benha, Al Qalyubiyah, Egypt.
⁵ Radiation Research of Polymer Chemistry Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt.

PMID: 38087036
DOI: 10.1007/s12011-023-03991-8

Abstract

Fluoride and aluminum are ubiquitous toxic metals with adverse reproductive effects. The citrus flavonoid hesperidin has protective activities but poor solubility and bioavailability. Nanoparticulate delivery systems can improve flavonoid effectiveness. We conducted this study to prepare a pH-responsive chitosan-based nanogel for hesperidin delivery and evaluate its effectiveness against sodium fluoride (NaF) and aluminum chloride (AlCl₃) induced testicular toxicity in mice. The nanogel was synthesized using 2 kGy gamma irradiation, enabling a size under 200 nm and enhanced hesperidin release at pH 6 matching testicular acidity. Male mice received 200 mg/kg AlCl₃ and 10 mg/kg NaF daily for 30 days. Hesperidin nanogel at 20 mg/kg was administered orally either prophylactically (pretreatment) or after intoxication (posttreatment). The results showed that AlCl₃ + NaF induced severe oxidative stress, hormonal disturbance, apoptosis, and endoplasmic reticulum stress, evidenced by significant changes in the studied parameters and testicular histological damage. Hesperidin nanogel administration significantly inhibited oxidative stress markers, restored luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels, and alleviated tissue damage compared to the intoxicated group. It also downregulated the expression level of pro-apoptotic genes Bax, caspase-3, caspase-9, and P38MAPK, while upregulating the expression level of the anti-apoptotic BCL2 gene. Endoplasmic reticulum stress sensors PERK, ATF6, and IRE-α were also downregulated by the nanogel. The chitosan-based nanogel enhanced the delivery and efficacy of poorly bioavailable hesperidin, exhibiting remarkable protective effects against AlCl₃ and NaF reproductive toxicity. This innovative nanosystem represents a promising approach to harnessing bioactive phytochemicals with delivery challenges, enabling protective effects against chemical-induced testicular damage.

Keywords: Aluminum; Fluoride; Hesperidin; Nanogel; Testicular damage.