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Maternal resveratrol supplementation ameliorates bisphenol A-induced atherosclerotic lesions formation in adult offspring ApoE−/− mice

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Abstract

Current evidence suggests that intrauterine bisphenol A (BPA) exposure increases the risk of developing cardiovascular diseases in later stages of life. The beneficial effect of resveratrol (Rsv) on developmental programming of atherosclerosis lesions formation in offspring is seldom reported. Hence, we sought to study the effect of maternal Rsv in ameliorating perinatal BPA exposure-induced atherosclerosis lesions formation in adult offspring using the apolipoprotein E-deficient (ApoE−/−) mice model. The pregnant ApoE−/− mice were allocated into three groups: control, BPA, BPA + resveratrol (BPA + Rsv). The BPA group mice received BPA in their drinking water (1 μg/ml). BPA + Rsv group mice received BPA in their drinking water (1 μg/ml) and were treated orally with Rsv (20 mg kg−1 day−1). All the treatments were continued throughout the gestation and lactation period. Quantitative analysis of Sudan IV-stained aorta revealed a significantly increased area of atherosclerotic lesions in both female (p < 0.01) and male adult offspring mice (p < 0.01) in the BPA group. Supplementation with Rsv significantly reduced the BPA-induced atherosclerotic lesion development in the female offspring mice (p < 0.05). Transmission electron microscopy revealed the presence of a significantly high incidence of autophagic endothelial, smooth muscle, and macrophage cells in the aorta of BPA-exposed mice. Rsv treatment reduced the incidence of autophagic cells in BPA-exposed mice. In conclusion, maternal Rsv supplementation significantly prevents the BPA-induced atherosclerotic lesions formation in a sex-dependent manner potentially by acting as an autophagy modulator.

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References

  • Aiken CE, Ozanne SE (2012) Sex differences in developmental programming models. Reproduction 145:R1–R13

    Article  Google Scholar 

  • Alonso-Magdalena P, Vieira E, Soriano S et al (2010) Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring. Environ Health Perspect 118:1243–1250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Angle BM, Do RP, Ponzi D et al (2013) Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation. Reprod Toxicol 42:256–268

    Article  CAS  PubMed  Google Scholar 

  • Argente-Arizon P, Ros P, Diaz F et al (2016) Age and sex dependent effects of early overnutrition on metabolic parameters and the role of neonatal androgens. Biol Sex Differ 7:26

    Article  PubMed  PubMed Central  Google Scholar 

  • Baird J, Jacob C, Barker M et al (2017) Developmental origins of health and disease: a lifecourse approach to the prevention of non-communicable diseases. Healthcare 5:14

    Article  PubMed Central  Google Scholar 

  • Batista TM, Alonso-Magdalena P, Vieira E et al (2012) Short-term treatment with bisphenol-A leads to metabolic abnormalities in adult male mice. PLoS ONE 7:e33814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boocock DJ, Faust GE, Patel KR et al (2007) Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomark Prev 16:1246–1252

    Article  CAS  Google Scholar 

  • Bourque SL, Dolinsky VW, Dyck JR, Davidge ST (2012) Maternal resveratrol treatment during pregnancy improves adverse fetal outcomes in a rat model of severe hypoxia. Placenta 33:449–452

    Article  CAS  PubMed  Google Scholar 

  • Diaz-Gerevini GT, Repossi G, Dain A, Tarres MC, Das UN, Eynard AR (2016) Beneficial action of resveratrol: how and why? Nutrition 32:174–178

    Article  CAS  PubMed  Google Scholar 

  • Dodds EC, Lawson W (1936) Synthetic estrogenic agents without the phenanthrene nucleus. Nature 137:996

    Article  CAS  Google Scholar 

  • Duewell P, Kono H, Rayner KJ et al (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–1361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Estampador AC, Franks PW (2014) Genetic and epigenetic catalysts in early-life programming of adult cardiometabolic disorders. Diabetes Metab Syndr Obes 7:575–586

    PubMed  PubMed Central  Google Scholar 

  • Fan E, Zhang L, Jiang S, Bai Y (2008) Beneficial effects of resveratrol on atherosclerosis. J Med Food 11:610–614

    Article  CAS  PubMed  Google Scholar 

  • Fang C, Ning B, Waqar AB et al (2014) Bisphenol A exposure enhances atherosclerosis in WHHL rabbits. PLoS ONE 9:e110977

    Article  PubMed  PubMed Central  Google Scholar 

  • Fang C, Ning B, Waqar AB et al (2015) Bisphenol A exposure induces metabolic disorders and enhances atherosclerosis in hyperlipidemic rabbits. J Appl Toxicol 35:1058–1070

    Article  CAS  PubMed  Google Scholar 

  • Gluckman PD, Hanson MA, Pinal C (2005) The developmental origins of adult disease. Matern Child Nutr 3:130–141

    Article  Google Scholar 

  • Grootaert MOJ, Roth L, Schrijvers DM, De Meyer GRY, Martinet W (2018) Defective autophagy in atherosclerosis: to die or to senesce? Oxid Med Cell Longev 2018:7687083

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo C, Li C, Myatt L, Nathanielsz PW, Sun K (2012) Sexually dimorphic effects of maternal nutrient reduction on expression of genes regulating cortisol metabolism in fetal baboon adipose and liver tissues. Diabetes 62:1175–1185

    Article  PubMed  Google Scholar 

  • Han C, Hong YC (2016) Bisphenol A, hypertension, and cardiovascular diseases: epidemiological, laboratory, and clinical trial evidence. Curr Hypertens Rep 18:11

    Article  PubMed  Google Scholar 

  • Hassanpour M, Rahbarghazi R, Nouri M, Aghamohammadzadeh N, Safaei N, Ahmadi M (2019) Role of autophagy in atherosclerosis: foe or friend? J Inflamm (lond) 16:8

    Article  Google Scholar 

  • Hsu CN, Hou CY, Tain YL (2021) Preventive aspects of early resveratrol supplementation in cardiovascular and kidney disease of developmental origins. Int J Mol Sci 22:4210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Juan ME, Vinardell MP, Planas JM (2002) The daily oral administration of high doses of trans-resveratrol to rats for 28 days is not harmful. J Nutr 132:257–260

    Article  CAS  PubMed  Google Scholar 

  • Kim MJ, Moon MK, Kang GH et al (2014) Chronic exposure to bisphenol A can accelerate atherosclerosis in high-fat-fed apolipoprotein E knockout mice. Cardiovas Toxicol 14:120–128

    Article  CAS  Google Scholar 

  • Klionsky DJ, Cuervo AM, Seglen PO (2007) Methods for monitoring autophagy from yeast to human. Autophagy 3:181–206

    Article  CAS  PubMed  Google Scholar 

  • Kurz T, Terman A, Brunk UT (2007) Autophagy, ageing and apoptosis: the role of oxidative stress and lysosomal iron. Arch Biochem Biophys 462:220–230

    Article  CAS  PubMed  Google Scholar 

  • Lin R, Wu D, Wu FJ et al (2019) Non-alcoholic fatty liver disease induced by perinatal exposure to bisphenol a is associated with activated mTOR and TLR4/NF-κB signaling pathways in offspring rats. Front Endocrinol 10(10):620

    Article  Google Scholar 

  • Lind PM, Lind L (2011) Circulating levels of bisphenol A and phthalates are related to carotid atherosclerosis in the elderly. Atherosclerosis 218:207–213

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Cao Y, Tong T et al (2015) Autophagy in atherosclerosis: a phenomenon found in human carotid atherosclerotic plaques. Chin Med J (engl) 128:69–74

    Article  CAS  Google Scholar 

  • Liu TY, Yu HR, Tsai CC et al (2020) Resveratrol intake during pregnancy and lactation re-programs adiposity and ameliorates leptin resistance in male progeny induced by maternal high-fat/high sucrose plus postnatal high-fat/high sucrose diets via fat metabolism regulation. Lip Health Dis 19:174

    Article  CAS  Google Scholar 

  • Ma Y, Xia W, Wang DQ et al (2013) Hepatic DNA methylation modifications in early development of rats resulting from perinatal BPA exposure contribute to insulin resistance in adulthood. Diabetologia 56:2059–2067

    Article  CAS  PubMed  Google Scholar 

  • Martel J, Ojcius DM, Chang CJ et al (2017) Anti-obesogenic and antidiabetic effects of plants and mushrooms. Nat Rev Endocrinol 13:149–160

    Article  CAS  PubMed  Google Scholar 

  • Martinet W, De Meyer GR (2009) Autophagy in atherosclerosis: a cell survival and death phenomenon with therapeutic potential. Circ Res 104:304–317

    Article  CAS  PubMed  Google Scholar 

  • Mela V, Llorente-Berzal A, Díaz F, Argente J, Viveros MP, Chowen JA (2012) Maternal deprivation exacerbates the response to a high fat diet in a sexually dimorphic manner. PLoS ONE 7(11):e48915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melzer D, Gates P, Osborne NJ et al (2012) Urinary bisphenol A concentration and angiography-defined coronary artery stenosis. PLoS ONE 7:e43378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meng Y, Yannan Z, Ren L, Qi S, Wei W, Lihong J (2020) Adverse reproductive function induced by maternal BPA exposure is associated with abnormal autophagy and activating inflamation via mTOR and TLR4/NF-κB signaling pathways in female offspring rats. Reprod Toxicol 96:185–194

    Article  CAS  PubMed  Google Scholar 

  • Mitchinson MJ (1982) Insoluble lipids in human atherosclerotic plaques. Atherosclerosis 45:11–15

    Article  CAS  PubMed  Google Scholar 

  • Miyawaki J, Sakayama K, Kato H, Yamamoto H, Masuno H (2007) Perinatal and postnatal exposure to bisphenol a increases adipose tissue mass and serum cholesterol level in mice. J Atheroscler Thromb 14:245–252

    Article  CAS  PubMed  Google Scholar 

  • Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147:728–741

    Article  CAS  PubMed  Google Scholar 

  • Mohanta S, Yin C, Weber C, Hu D, Habenicht AJ (2016) Aorta atherosclerosis lesion analysis in hyperlipidemic mice. Bio Protoc 6:e1833

    Article  PubMed  Google Scholar 

  • Napoli C, D’ Armiento FP, Mancini FP, Postiglione A, Witztum JL, Palumbo G et al (1997) Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest 100:2680–2690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Napoli C, Glass CK, Witztum JL, Deutsch R, D’Armiento FP, Palinski W (1999) Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: fate of early lesions in children (FELIC) STUDY. Lancet 9(354):1234–1241

    Article  Google Scholar 

  • Oliveira ALB, Monteiro VVS, Navegantes-Lima KC et al (2017) Resveratrol role in autoimmune disease-a mini-review. Nutrients 9:1306

    Article  PubMed Central  Google Scholar 

  • Paigen B, Plump AS, Rubin EM (1994) The mouse as a model for human cardiovascular disease and hyperlipidemia. Curr Opin Lipidol 5:258–264

    Article  CAS  PubMed  Google Scholar 

  • Pattison JS, Robbins J, Martinez J, Tabas I (2012) Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab 15:545–553

    Article  PubMed  PubMed Central  Google Scholar 

  • Penumathsa SV, Thirunavukkarasu M, Koneru S et al (2007) Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat. J Mol Cell Cardiol 42:508–516

    Article  CAS  PubMed  Google Scholar 

  • Perrotta I (2013) The use of electron microscopy for the detection of autophagy in human atherosclerosis. Micron 50:7–13

    Article  PubMed  Google Scholar 

  • Quan C, Wang C, Duan P et al (2017) Bisphenol a induces autophagy and apoptosis concurrently involving the Akt/mTOR pathway in testes of pubertal SD rats. Environ Toxicol 32:1977–1989

    Article  CAS  PubMed  Google Scholar 

  • Rasdi Z, Kamaludin R, Ab Rahim S et al (2020) The impacts of intrauterine bisphenol A exposure on pregnancy and expression of miRNAs related to heart development and diseases in animal model. Sci Rep 10:5882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rezaei Farimani A, Saidijam M, Goodarzi MT et al (2015) Effect of resveratrol supplementation on the SNARE proteins expression in adipose tissue of stroptozotocin-nicotinamide induced type 2 diabetic rats. Iran J Med Sci 40:248–55

    PubMed  PubMed Central  Google Scholar 

  • Rochester JR (2013) Bisphenol A and human health: a review of the literature. Reprod Toxicol 42:132–155

    Article  CAS  PubMed  Google Scholar 

  • Ros P, Diaz F, Freire-Regatillo A et al (2018) Resveratrol intake during pregnancy and lactation modulates the early metabolic effects of maternal nutrition differently in male and female offspring. Endocrinology 159:810–825

    Article  CAS  PubMed  Google Scholar 

  • Sanches-Silva A, Testai L, Nabavi SF et al (2020) Therapeutic potential of polyphenols in cardiovascular diseases: regulation of mTOR signaling pathway. Pharmacol Res 152:104626

    Article  CAS  PubMed  Google Scholar 

  • Shah A, Reyes LM, Morton JS, Fung D, Schneider J, Davidge ST (2016) Effect of resveratrol on metabolic and cardiovascular function in male and female adult offspring exposed to prenatal hypoxia and a high-fat diet. J Physiol 594:1465–1482

    Article  CAS  PubMed  Google Scholar 

  • Shankar A, Teppala S, Sabanayagam C (2012) Bisphenol A and peripheral arterial disease: results from the NHANES. Environ Health Perspect 120:1297–1300

    Article  PubMed  PubMed Central  Google Scholar 

  • Song D, Chen Y, Wang B et al (2019) Bisphenol A inhibits autophagosome-lysosome fusion and lipid droplet degradation. Ecotoxicol Environ Saf 15(183):109492

    Article  Google Scholar 

  • Sui Y, Park SH, Helsley RN et al (2014) Bisphenol A increases atherosclerosis in pregnane X receptor-humanized ApoE deficient mice. J Am Heart Assoc 3:e000492

    Article  PubMed  PubMed Central  Google Scholar 

  • Sui Y, Park SH, Wang F, Zhou C (2018) Perinatal bisphenol A exposure increases atherosclerosis in adult male PXR-humanized mice. Endocrinology 159:1595–1608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szkudelski T, Szkudelska K (2015) Resveratrol and diabetes: from animal to human studies. Biochim Biophys Acta 1852:1145–1154

    Article  CAS  PubMed  Google Scholar 

  • Takahashi O, Oishi S (2000) Disposition of orally administered 2, 2-Bis (4-hydroxyphenyl) propane (Bisphenol A) in pregnant rats and the placental transfer to fetuses. Environ Health Perspect 108:931–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takeda-Watanabe A, Kitada M, Kanasaki K, Koya D (2012) SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells. Biochem Biophys Res Commun 427:191–196

    Article  CAS  PubMed  Google Scholar 

  • Truong VL, Jun M, Jeong WS (2018) Role of resveratrol in regulation of cellular defense systems against oxidative stress. BioFactors 44:36–49

    Article  CAS  PubMed  Google Scholar 

  • Wallack L, Thornburg K (2016) Developmental origins, epigenetics, and equity: moving upstream. Matern Child Health J 20:935–940

    Article  PubMed  Google Scholar 

  • Wei J, Lin Y, Li Y et al (2011) Perinatal exposure to bisphenol A at reference dose predisposes offspring to metabolic syndrome in adult rats on a high-fat diet. Endocrinology 152:3049–3061

    Article  CAS  PubMed  Google Scholar 

  • Williams LD, Burdock GA, Edwards JA, Beck M, Bausch J (2009) Safety studies conducted on high-purity trans-resveratrol in experimental animals. Food Chem Toxicol 47:2170–2182

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Cao X, Zhu W et al (2016) Resveratrol enhances autophagic flux and promotes Ox-LDL degradation in HUVECs via upregulation of SIRT1. Oxid Med Cell Longev 2016:7589813

    Article  PubMed  PubMed Central  Google Scholar 

  • Zheng J, Xiao X, Zhang Q, Wang T, Yu M, Xu J (2017) Maternal low-protein diet modulates glucose metabolism and hepatic micrornas expression in the early life of offspring dagger. Nutrients 9:1–14

    Article  CAS  Google Scholar 

  • Zheng S, Feng Q, Cheng J, Zheng J (2018) Maternal resveratrol consumption and its programming effects on metabolic health in offspring mechanisms and potential implications. Biosci Rep 38:BSR20171741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu X, Wu C, Qiu S, Yuan X, Li L (2017) Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: systematic review and meta-analysis. Nutr Metab (lond) 14:60

    Article  Google Scholar 

  • Zou T, Chen D, Yang Q et al (2017) Resveratrol supplementation of high-fat diet-fed pregnant mice promotes brown and beige adipocyte development and prevents obesity in male offspring. J Physiol 595:1547–1562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Kawther Al Adawi from the department of Pathology, Sultan Qaboos University for her help in TEM. We also thank Taconic Biosciences, Inc. for providing ApoE−/− mice.

Funding

This study was funded by Internal Grant no. IG/MED/ANAT/18/01 from Sultan Qaboos University.

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Authors and Affiliations

  1. Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoudh, PO Box 35, Muscat, PC 123, Oman

    Srinivasa Rao Sirasanagandla & Mohamed Al Mushaiqri

  2. Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoudh, Muscat, 123, Oman

    Isehaq Al-Huseini

  3. Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoudh, Muscat, 123, Oman

    Nadia Al-Abri & Fatma Al-Ghafri

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  1. Srinivasa Rao Sirasanagandla
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  2. Isehaq Al-Huseini
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  3. Mohamed Al Mushaiqri
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  4. Nadia Al-Abri
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  5. Fatma Al-Ghafri
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Contributions

SRS, IAH, and MAM contributed to the study conception and design. SRS, IAH, and MAM conducted the animal experiments. SRS, IAH, NA and FA performed tissue processing, data collection and results analysis. SRS, IAH and MAM drafted the manuscript. NA and FA gave vital inputs to the manuscript. All authors commented on previous versions of the manuscript.

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Correspondence to Srinivasa Rao Sirasanagandla.

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All the animal experimental procedures of the present study were conducted in accordance with the international laws and policies and were performed after obtaining the approval from the Sultan Qaboos University Animal Ethical Committee (SQU/AEC/2016–17/12).

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Sirasanagandla, S.R., Al-Huseini, I., Al Mushaiqri, M. et al. Maternal resveratrol supplementation ameliorates bisphenol A-induced atherosclerotic lesions formation in adult offspring ApoE−/− mice. 3 Biotech 12, 36 (2022). https://doi.org/10.1007/s13205-021-03078-y

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