Resveratrol Mitigates Acrylonitrile-induced Thyroid and Adrenal Toxicity in Rats

Samer I. Sabeeh ^1*, Ahmed Q. Al-Awadi ¹

Resveratrol counters acrylonitrile's adverse effects, preserving thyroid and adrenal function, evidenced hormonally and histologically, suggesting therapeutic potential.

Abstract

Background: Acrylonitrile (AN) poses significant health risks as a potent multi-site carcinogen, causing toxicity in various organs including the brain, lung, liver, kidney, stomach, and adrenal glands. AN-induced oxidative stress and lipid peroxidation lead to DNA damage and organ dysfunction, including adrenal necrosis and haemorrhages. Resveratrol, a potent antioxidant, offers potential protection against acrylonitrile-induced damage. Method: This study utilized 55 adult male Sprague-Dawley rats divided into four groups: control, Resveratrol-treated, AN-treated, and AN + Resveratrol-treated. Animals were subjected to oral administration of AN or Resveratrol for 90 days. Serum levels of thyroid hormones (T3, T4, TSH) and adrenaline were measured using ELISA, while histopathological changes in thyroid and adrenal glands were examined microscopically. Results: AN exposure significantly decreased serum concentrations of T3, T4, TSH, and adrenaline, accompanied by histopathological alterations including necrotic follicles and adrenal congestion. Resveratrol treatment mitigated these effects, restoring hormone levels and preserving tissue architecture. Conclusion: Resveratrol exhibits protective effects against AN-induced toxicity by enhancing thyroid and adrenal hormone production and attenuating histopathological changes in thyroid and adrenal glands. Its antioxidant properties mitigate oxidative stress and maintain cellular homeostasis, suggesting its potential therapeutic utility in combating AN-related health hazards. Further research is warranted to elucidate the mechanisms underlying Resveratrol's protective effects on adrenal vascular function.

Keywords: Acrylonitrile, Resveratrol, Thyroid, Adrenal, Toxicity

References

A.S. Abdul Majid, Elham Farsi, N.Vijayalakshmi, S.A. Syed Amran, M.M. Kanakal, Z.T.Zainudeen. (2019). Evaluation of Safety and Efficacy of Labeesity® for Weight Management and Fatigue in an Obese Female Patient with Hypothyroidism: A Case Report, Journal of Angiotherapy, 3(1), pp. 132-137

Abdulla JM, Al-Okaily BN. Histomorphometric and histopathological alterations of rat testis following exposure to hydrogen‎ peroxide: Protective role of resveratrol supplement. The Iraqi Journal of Veterinary Medicine. 2022 Jul 28;46(1):17-23.

Al-Azzawi AM, Al-Tamimi EO, Ali RA. Synthesis and copolymerization of several N-substituted acrylamides. Um-Salama Science Journal. 2008;5(4):619-26.

Al-Azzawi, A. M., & Yaseen, H. K. (2016). Synthesis and Characterization of Several New Copolymers Based on Maleimides Bearing 1, 3, 4-Oxadiazole Moiety. Iraqi Journal of Science, 2604-2616.

Albertini, R. J., Kirman, C. R., & Strother, D. E. (2023). Acrylonitrile’s genotoxicity profile: mutagenicity in search of an underlying molecular mechanism. Critical Reviews in Toxicology, 1-48.

Albertini, R. J., Kirman, C. R., & Strother, D. E. (2023). Acrylonitrile’s genotoxicity profile: mutagenicity in search of an underlying molecular mechanism. Critical Reviews in Toxicology, 1-48.

Alghetaa, H., Mohammed, A., Sultan, M., Busbee, P., Murphy, A., Chatterjee, S., ... & Nagarkatti, P. (2018). Resveratrol protects mice against SEB-induced acute lung injury and mortality by miR-193a modulation that targets TGF-β signalling. Journal of cellular and molecular medicine, 22(5), 2644-2655.

Arlandson, M., Decker, T., Roongta, V. A., Bonilla, L., Mayo, K. H., MacPherson, J. C., ... & Slungaard, A. (2001). Eosinophil peroxidase oxidation of thiocyanate: characterization of major reaction products and a potential sulfhydryl-targeted cytotoxicity system. Journal of Biological Chemistry, 276(1), 215-224.

Bancroft JD, Gamble M. Theory and practice of histological techniques. Spencer LT, Bancroft JD. 6 th  ed. London: Churchill Livingstone2007; 179.

Bates, C. A., Haber, L. T., Moore, M. M., Schoeny, R., & Maier, A. (2023). Development of a framework for risk assessment of dietary carcinogens. Food and Chemical Toxicology, 180, 114022.

Cai YJ, Fang JG, Ma LP, Yang L, Liu ZL. Inhibition of free radical-induced peroxidation of rat liver microsomes by resveratrol and its analogues. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2003 Jan 20;1637(1):31-8.

Chandra, A. K., Ghosh, R., Chatterjee, A., & Sarkar, M. (2007). Amelioration of vanadium-induced testicular toxicity and adrenocortical hyperactivity by vitamin E acetate in rats. Molecular and Cellular Biochemistry, 306, 189-200.

Chang CC, Chang CY, Huang JP, Hung LM. Effect of resveratrol on oxidative and inflammatory stress in liver and spleen of streptozotocin-induced type 1 diabetic rats. Chin J Physiol. 2012 Jun 1;55(3):192-201.

Dang, Y., Li, Z., Wei, Q., Zhang, R., Xue, H., & Zhang, Y. (2018). Protective effect of apigenin on acrylonitrile-induced inflammation and apoptosis in testicular cells via the NF-κB pathway in rats. Inflammation, 41, 1448-1459.

Dong, W. W., Liu, Y. J., Lv, Z., Mao, Y. F., Wang, Y. W., Zhu, X. Y., & Jiang, L. (2015). Lung endothelial barrier protection by resveratrol involves inhibition of HMGB1 release and HMGB1-induced mitochondrial oxidative damage via an Nrf2-dependent mechanism. Free Radical Biology and Medicine, 88, 404-416.

European Chemicals Agency (ECHA). (2018). Background document in support of the Committee for Risk Assessment (RAC) evaluation of limit values for acrylonitrile in the workplace.

Farokhi,  F.  and  Taravati,  A.  2014.  Pesticide exposure  and  thyroid  function  in  adult  male sprayers.  International  Journal  of  Medical Investigation, 3 (4): 127 - 132.

Firouzi, E., Hajifatheali, H., Ahmadi, E., & Marefat, M. (2020). An Overview of Acrylonitrile Production Methods: Comparison of Carbon Fiber Precursors and Marketing. Mini-Reviews in Organic Chemistry, 17(5), 570-588.

Floreani, M., Napoli, E., Quintieri, L., & Palatini, P. (2003). Oral administration of trans-resveratrol to guinea pigs increases cardiac DT-diaphorase and catalase activities, and protects isolated atria from menadione toxicity. Life sciences, 72(24), 2741-2750.

Goldhaber, S., Dorman, D., Gardner, D., & Adeshina, F. (2009). Provisional advisory levels (PALs) for acrylonitrile. Inhalation toxicology, 21(sup3), 17-55.

Goswami SK, Das DK. Resveratrol and chemoprevention. Cancer Lett. 2009; 284:1-6.

Greaves, P. (2011). Histopathology of preclinical toxicity studies: interpretation and relevance in drug safety evaluation. Academic Press.

Gutiérrez-Pérez, A., Cortés-Rojo, C., Noriega-Cisneros, R., Calderón-Cortés, E., Manzo-Avalos, S., Clemente-Guerrero, M., ... & Saavedra-Molina, A. (2011). Protective effects of resveratrol on calcium-induced oxidative stress in rat heart mitochondria. Journal of bioenergetics and biomembranes, 43, 101-107.

Hamlin, M. H. (1990). 31. Adrenal gland. Pathology of the Fischer rat, 501-518.

Hughes, C. G., Morandi, A., Girard, T. D., Riedel, B., Thompson, J. L., Shintani, A. K., ... & Pandharipande, P. P. (2013). Association between endothelial dysfunction and acute brain dysfunction during critical illness. The Journal of the American Society of Anesthesiologists, 118(3), 631-639.

Humadi AA, AL-Kaisei BI, Humadi TJ. ACRYLONITRILE TESTICULAR SEMINOMA IN BEAGLE MALE DOGS (PATHOLOGICAL AND HORMONAL ASSAY). Plant Archives (09725210). 2020 Apr 1;20(1).

Hwang, J. S., & Chang, H. N. (1989). Biotransformation of acrylonitrile to acrylamide using immobilized whole cells of Brevibacterium CH1 in a recycle fed-batch reactor. Biotechnology and bioengineering, 34(3), 380-386.

Ibrahima, S. S., Saidb, A. M., & Aboubakrc, M. (2018). Ameliorative Effect of Ascorbic Acid and/or Ginseng Extract against Thyroid Gland Toxicity Induced by Potassium Dichromate in Rats. Journal of pharmacology and clinical research, 5(1), 1-6.

International Programme on Chemical Safety I. Acrylonitrile Concise international chemical assessment document 39. Geneva: WHO 2002.

Islam, M. R., Yesmin, T., Prapty, A. N., Biswash, M. A. R., Rana, M. S., & Rashid, M. H. O. (2024). Natural Environmental Sources of Resveratrol and Its Therapeutic Role in Cancer Prevention. Australian Herbal Insight, 7(1), 1–11, 9931.

Jawad.K.Arrak.(2010). Effect of Ellagic Acid Extracted from Pomegranate (Punica granatum L.) on Thyroid and Parathyroid Gland of Adult Rats Exposed to Lead Acetate. Kufa Journal For Veterinary Medical Sciences, 1(1):39-51.

Kaneko, J. L., Harvery, T. W and Michael, L. B.  1997.  Clinical  iochemistry  of  domestic animals.  5th  ed.  Academic  Press,  Inc.  San Diego,  London,  Boston, New York. Pp.: 54 – 65

Khayoon HA, Al-Rekabi FM. Cytotoxic effect of resveratrol on colorectal cancer cell line. The Iraqi Journal of Veterinary Medicine. 2020 Jun 28;44(1):68-74.

Khudair NT, Al-Okaily BN. Renal ameliorating effect of resveratrol in hydrogen peroxide induced male rats. Iraqi Journal of Veterinary Sciences. 2022 Jul 1;36(3):571-7.

Kim, S. M., & Choi, K. C. (2020). Acrylonitrile induced cell cycle arrest and apoptosis by promoting the formation of reactive oxygen species in human choriocarcinoma cells. The Journal of Toxicological Sciences, 45(11), 713-724.

Kobets, T., Iatropoulos, M. J., & Williams, G. M. (2022). Acrylonitrile induction of rodent neoplasia: Potential mechanism of action and relevance to humans. Toxicology Research and Application, 6, 23978473211055363.

Kobets, T., Iatropoulos, M. J., & Williams, G. M. (2022). Acrylonitrile induction of rodent neoplasia: Potential mechanism of action and relevance to humans. Toxicology Research and Application, 6, 23978473211055363.

La Mura, V., Pasarín, M., Meireles, C. Z., Miquel, R., Rodríguez-Vilarrupla, A., Hide, D., ... & Abraldes, J. G. (2013). Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction. Hepatology, 57(3), 1172-1181.

Laast, V. A., Larsen, T., Allison, N., Hoenerhoff, M. J., & Boorman, G. A. (2014). Distinguishing cystic degeneration from other aging lesions in the adrenal cortex of Sprague-Dawley rats. Toxicologic Pathology, 42(5), 823-829.

Ma, Q.,  Tipping,  R.  H  and  Boulet,  C.  2006. Irreducible correlation functions of the matrix in  the  coordinate  representation:  Application in  calculating  Lorentzian  half  widths  and shifts. Journal of Chemistry and Physics, 124: 014 - 019.

Mahmod WS, Al-Jumaili EF, Mohamad NB. Qualitative and Quantitative evaluation of the extracted flavonoids in Iraqi-Sumac (Rhus coriaria L.). Iraqi journal of biotechnology. 2022 Aug 7;21(1).

Mannam, P., Zhang, X., Shan, P., Zhang, Y., Shinn, A. S., Zhang, Y., & Lee, P. J. (2013). Endothelial MKK3 is a critical mediator of lethal murine endotoxemia and acute lung injury. The Journal of Immunology, 190(3), 1264-1275.

Moridi, H., Karimi, J., Sheikh, N., Goodarzi, M. T., Saidijam, M., Yadegarazari, R., ... & Rezaei, A. (2015). Resveratrol-dependent down-regulation of receptor for advanced glycation end-products and oxidative stress in kidney of rats with diabetes. International journal of endocrinology and metabolism, 13(2).

Nawras A. Alwan*, Jassim M. A. Alkalby and Eman Aboud Al-Masoudi.(2016). EFFECT OF ACRYLAMIDE ON THYROID AND LIVER FUNCTIONS IN ADULT MALE RATS. Asian Journal of Multidisciplinary Research, 2(4):673-680.

Omidian, M., Abdolahi, M., Daneshzad, E., Sedighiyan, M., Aghasi, M., Abdollahi, H., ... & Mahmoudi, M. (2020). The effects of resveratrol on oxidative stress markers: a systematic review and meta-analysis of randomized clinical trials. Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets-Immune, Endocrine & Metabolic Disorders), 20(5), 718-727.

Patani, A., Balram, D., Yadav, V. K., Lian, K. Y., Patel, A., & Sahoo, D. K. (2023). Harnessing the power of nutritional antioxidants against adrenal hormone imbalance-associated oxidative stress. Frontiers in Endocrinology, 14.

  Peng XL, Xu J, Sun XF, Ying CJ, Hao LP. Analysis of trans-resveratrol and trans-piceid in vegetable foods using high-performance liquid chromatography. Int J Food Sci Nutr. 2015;66:729-735.

Pisoschi, A. M., Pop, A., Iordache, F., Stanca, L., Predoi, G., & Serban, A. I. (2021). Oxidative stress mitigation by antioxidants-an overview on their chemistry and influences on health status. European Journal of Medicinal Chemistry, 209, 112891.

Polito, A., Lorin de la Grandmaison, G., Mansart, A., Louiset, E., Lefebvre, H., Sharshar, T., & Annane, D. (2010). Human and experimental septic shock are characterized by depletion of lipid droplets in the adrenals. Intensive care medicine, 36, 1852-1858.

Puppel, K., Kapusta, A., & Kuczynska, B. (2015). The etiology of oxidative stress in the various species of animals, a review. Journal of the Science of Food and Agriculture, 95(11), 2179-2184.

Ramadhan, S. J., & Khudair, K. (2018). Effect of betaine and or acrylamide on serum lipids profile and antioxidant status of female rats. Indian J Nat Sci, 9, 51.

RH ElBakry and SM Tawfik (2014) Histological study of the effect of potassium dichromate on the thyroid follicular cells of adult male albino rat and the possible protective role of ascorbic acid (vitamin C). J Microscopy Ultrastructure 2(3): 137-150

Rieder SA, Nagarkatti P, Nagarkatti M. Multiple anti-inflammatory pathways triggered by resveratrol lead to amelioration of staphylococcal enterotoxin B-induced lung injury. British journal of pharmacology. 2012 Nov;167(6):1244-58.

Santos, M. A., Franco, F. N., Caldeira, C. A., de Araújo, G. R., Vieira, A., Chaves, M. M., & Lara, R. C. (2021). Antioxidant effect of Resveratrol: Change in MAPK cell signaling pathway during the aging process. Archives of gerontology and geriatrics, 92, 104266.

Serrano-Nascimento, C., & Nunes, M. T. (2022). Perchlorate, nitrate, and thiocyanate: Environmental relevant NIS-inhibitors pollutants and their impact on thyroid function and human health. Frontiers in endocrinology, 13, 995503.

Shi, Y., Bai, J., Dang, Y., Bai, Q., Zheng, R., Chen, J., & Li, Z. (2021). Protection of apigenin against acrylonitrile-induced sperm and testis injury in rats: involvement of activation of ASK1-JNK/p38 signaling pathway. Toxicology Research, 10(2), 159-168.

Shniakat WN, Al-Khateeb EH, Numan NA, Abbas MM, Shakya A. Cytotoxic Evaluation of Doxorubicin Combination with Baicalein and Resveratrol Against Hct116 and Hepg2 Cancer Cell Lines (Conference Paper). Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512). 2022;31(Suppl.):92-9.

Somaya M. Eshtiwi. (2024). Treatment of Hypothyroidism with Flavonoid Rich Extract of Fucus vesiculosus L Algae in Adult Rats, Journal of Angiotherpay, 8(3), 1-10, 9530

Srivalsa Bhaskaran, Kamaal Mohideen Khan, Karthik V, Mani Shanthini, (2021), Hypothyroidism Presenting as Reversible Renal Impairment, Journal of Angiotherapy, 5(2), 2161

Szabo, S., & Sandor, Z. (1997). Chemically induced lesions in the adrenal cortex. Endocrine toxicology.

Szabo, S., Gallagher, G. T., Silver, E. H., Maull, E. A., Horner, H. C., Komanicky, P., ... & Kovacs, K. (1984). Subacute and chronic action of acrylonitrile on adrenals and gastrointestinal tract: biochemical, functional and ultrastructural studies in the rat. Journal of applied toxicology, 4(3), 131-140.

Verma, Y., & Rana, S. V. S. (2009). Endocrinal toxicity of industrial solvents–a mini review.

Vinay Jaiswal, Prachi Gurudiwan. (2023). Identifying Thyroid Dysfunction Using Standard Laboratory Testings – A Systematic Review, Journal of Angiotherapy, 7(2), 1-8, 9409.

Wade, M. G., Parent, S., Finnson, K. W., Foster, W., Younglai, E., McMahon, A., ... & Hughes, C. (2002). Thyroid toxicity due to subchronic exposure to a complex mixture of 16 organochlorines, lead, and cadmium. Toxicological Sciences, 67(2), 207-218.

Westermann, J., Hubl, W., Kaiser, N., & Salewski, L. (2002). Simple, rapid and sensitive determination of epinephrine and norepinephrine in urine and plasma by non-competitive enzyme immunoassay, compared with HPLC method. Clinical laboratory, 48(1-2), 61-72.

Yuan, Z., Zhang, X., Yao, Q., Zhang, Y., & Fu, Y. (2019). Production of acetonitrile via catalytic fast pyrolysis of biomass derived polylactic acid under ammonia atmosphere. Journal of Analytical and Applied Pyrolysis, 140, 376-384.

Zhang, H. X., Duan, G. L., Wang, C. N., Zhang, Y. Q., Zhu, X. Y., & Liu, Y. J. (2014). Protective effect of resveratrol against endotoxemia-induced lung injury involves the reduction of oxidative/nitrative stress. Pulmonary Pharmacology & Therapeutics, 27(2), 150-155.

Zhao, F., Dang, Y., Zhang, R., Jing, G., Liang, W., & Li, Z. (2019). Apigenin attenuates acrylonitrile-induced neuro-inflammation in rats: involved of inactivation of the TLR4/NF-κB signaling pathway. International immunopharmacology, 75, 105697.