Dyslipidemia’s influence on the secretion ovarian’s steroids in female mice

Authors

DOI:

https://doi.org/10.33448/rsd-v10i13.21369

Keywords:

Hypercholesterolemia; hypercholesterolemia; Estrogen; estrogen; Progesterone; progesterone; Oxidative stress.; oxidative stress

Abstract

Introduction: The synthesis ovarian’s steroids is a process thats depends on the supply of cholesterol. Objective: to evaluate the influence of dyslipidemia on the secretion ovarian’s steroids. Methodology: wild female mice were used (C57BL6) and LDL (LDLR-/-), which they were separated into 4 groups (n = 10): WTS: fed a standard diet; WTHL: fed a high-fat diet; KOS: fed a standard diet; KOHL: fed a high-fat diet. After 60 days, the estrous cycle was analyzed and after anesthetized, blood was collected for the to assess the lipid profile, glucose, plasma insulin level and HOMA index was calculated. In addition, plasma levels of C-reactive protein, estrogen and progesterone were determined. Results: The hyperlipidic diet in both the WTHL and the KOHL group generated hypercholesterolemia when compared to the WTS and KOS, respectively, with a decrease in HDLc, associated with an increase in CRP levels. Severe hypercholesterolemia in the KOHL group generated insulin resistance, marked by an increase in HOMAir. Food hypercholesterolemia in the WTHL group, food and genetics in the KOHL group, compared to their WTS and KOS controls, was definitive in reducing plasma levels of estrogen and progesterone. The genetic hypercholesterolemia associated with insulin resistance observed in the KOS and KOHL groups reduced the levels of progesterone, this reduction being more severe in the KOHL group, which had the highest HOMAir. Conclusion: dyslipidemia affected ovarian steroidogenesis in mice by means of oxidative stress, inflammation and insulin resistance and / or by decreasing HDL cholesterol levels.

References

Aleisa, A. M., et al. (2013). Ameliorative effects of rutin and ascorbic acid combination on hypercholesterolemia-induced hepatotoxicity in female rats. African Journal of Pharmacy and Pharmacology. v. 7, n. 6, p. 280-288.

Alsheikh-ali, A. A., Kuvin, J. T. & Karas, R. H. (2005). High-density lipoprotein cholesterol in the cardiovascular equation: does the “good” still count?. Atherosclerosis. v. 180, n. 2, p. 217-223.

Andersen, J. M. & Dietschy, J. M. (1978). Relative importance of high and low density lipoproteins in the regulation of cholesterol synthesis in the adrenal gland, ovary, and testis of the rat. Journal of Biological Chemistry. v. 253, n. 24, p. 9024-9032.

Archuleta, T. L., et al. (2009). Oxidant stress-induced loss of IRS-1 and IRS-2 proteins in rat skeletal muscle: role of p38 MAPK. Free Radical Biology and Medicine. v. 47, n. 10, p. 1486-1493.

Argov, N. & Sklan, D. (2004). Expression of mRNA of Lipoprotein Receptor Related Protein 8, Low Density Lipoprotein Receptor, and Very Low Density Lipoprotein Receptor in Bovine Ovarian Cells During Follicular Development and Corpus Luteum Formation and Regression. Molecular Reproduction And Development. v. 68, p.169–175.

Assmann, G., Gotto Jr & Antonio M. (2004). HDL cholesterol and protective factors in atherosclerosis. Circulation. v. 109, n. 23_suppl_1, p. III-8-III-14.

Azhar, S., Leers-Sucheta, S. & Reaven, E. (2003). Cholesterol uptake in adrenal and gonadal tissues: the SR-BI and ‘selective’pathway connection. Front Biosci. v. 8, p. s998-1029.

Bhatia, B. & Price, C. A. (2001). Insulin alters the effects of follicle stimulating hormone on aromatase in bovine granulosa cells in vitro. Steroids. v. 66, n. 6, p. 511-519.

Brantmeier, S. A.; Grummer, R. R. & Ax, R. L. (1987). Concentrations of high density lipoproteins vary among follicular sizes in the bovine. Journal of dairy science. v. 70, n. 10, p. 2145-2149.

Breslow, J. L. (1993). Transgenic mouse models of lipoprotein metabolism and atherosclerosis. National Academy of Sciences. v. 90, n. 18, p. 8314-8318.

Carmeliet, P., Moons, L. & Collen, D. (1998). Mouse models of angiogenesis, arterial stenosis, atherosclerosis and hemostasis. Cardiovascular research. v. 39, n. 1, p. 8-33,

Chapman, M. J. (2004). Are the effects of statins on HDL-cholesterol clinically relevant?. European Heart Journal Supplements. v. 6, n. suppl_C, p. C58-C63.

Chaves, R. N., et al. (2011). Implicações da insulina na função ovariana e desenvolvimento embrionário. Acta Veterinaria Brasilica. v. 5, n. 2, p. 136-146.

Christison, J. et al. (1996). Rapid reduction and removal of HDL-but not LDL-associated cholesteryl ester hydroperoxides by rat liver perfused in situ. Biochemical Journal, v. 314, n. 3, p. 739-742.

Dandona, P. et al. (2013). Insulin infusion suppresses while glucose infusion induces toll like receptors and high mobility group-B1 protein expression in mononuclear cells of type 1 diabetics. American Journal of Physiology – Endocrinology and Metabolism. v. 304, p. E810 – E818.

Diamanti-kandarakis, E. & Dunaif, A. (2012). Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocrine reviews. v. 33, n. 6, p. 981-1030.

Dyer, C. A. & Curtiss, L. K. (1988). Apoprotein E-rich high density lipoproteins inhibit ovarian androgen synthesis. J Biol Chem. v. 263, n. 22, p. 10965–10973.

Egnatchik, R. A. et al. (2014). Palmitate-induced activation of mitochondrial metabolism promotes oxidative stress and apoptosis in H4IIEC3 rat hepatocytes. Metabolism. v. 63, n. 2, p. 283-295.

Fazio, S.& Linton, M. F. (2001). Mouse models of hyperlipidemia and atherosclerosis. Frontiers in bioscience: a journal and virtual library. v. 6, p. D515-25.

Friedewald, W.T., Levy, R. I. & Fredrickson, D. S. (1972). Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical chemistry. v. 18, n. 6, p. 499-502.

Garcia, J. A. D. et al. (2011). Efeito anti-inflamatório da lipoproteína de alta densidade no sistema cardiovascular de camundongos hiperlipidêmicos (Antiinflammatory effect of high density lipoprotein on the cardiovascular system of hyperlipidemic mice). Rev Port Cardiol. v. 30, n. 10, p. 763–769.

Garcia, J. A.D. et al. (2008). S-nitroso-n-acetylcysteine (SNAC) prevents myocardial alterations in hypercholesterolemic LDL receptor knockout mice by antiinflammatory action. Journal of cardiovascular pharmacology. v. 51, n. 1, p. 78-85, 2008.

Guo, T. et al. (2015). Low-density lipoprotein receptor affects the fertility of female mice. Reproduction, Fertility and Development. v. 27, n. 8, p. 1222-1232.

Hedrick, C. C. et al. (2001). In vivo interactions of apoA-II, apoA-I, and hepatic lipase contributing to HDL structure and antiatherogenic functions. Journal of lipid research. v. 42, n. 4, p. 563-570.

Henderson, K. M., Gorban, A. M. S & Boyd, G. S. (1981). Effect of LH factors regulating ovarian cholesterol metabolism and progesterone synthesis in PMSG-primed immature rats. Reproduction. v. 61, n. 2, p. 373-380.

Henriksen, E.J., Diamond-Stanic, Maggie K. & Marchionne, E. M. (2011). Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radical Biology and Medicine. v. 51, n. 5, p. 993-999.

Hwang, J. & Menon, K. M. (1983). Characterization of low density and high density lipoprotein receptors in the rat corpus luteum and regulation by gonadotropin. Journal of Biological Chemistry. v. 258, n. 13, p. 8020-8027.

Ishibashi, S. et al. (1993). Hypercholesterolemia in Low Density Lipoprotein Receptor Knockout Mice and its Reversal by Adenovirus-mediated Gene Delivery. The Journal of Clinical Investigation. v.92, p. 883-893.

Ishibashi, S. et al. (1994). The two-receptor model of lipoprotein clearance: tests of the hypothesis in" knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proceedings of the National Academy of Sciences. v. 91, n. 10, p. 4431-4435.

Lima, J. C. C. et al. (2000). Usando proteína C reativa de alta sensibilidade (PCR-AS) como preditor de doença cardiovascular. Newslab. v. 41, p. 164-166,

Louhio, H. et al. (2000). The effects of insulin, and insulin-like growth factors I and II on human ovarian follicles in long-term culture. Molecular human reproduction. v. 6, n. 8, p. 694-698.

Martins, A. M. et al. (2020). Grape juice attenuates left ventricular hypertrophy in dyslipidemic mice. Plos one. v. 15, n. 9, p. e0238163.

Miettinen, H. E. Rayburn, H. & Krieger M. (2001). Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)-deficient mice. J Clin Invest. 108(11):1717-22.

Miller, W. L.; Auchus, R. J. (2011). The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Ver. v. 32, p. 81–151.

Myers, M. G. et al. (1991). The insulin receptor functions normally in Chinese hamster ovary cells after truncation of the C terminus. Journal of Biological Chemistry. v. 266, n. 16, p. 10616-10623.

Nofer, J. R. et al. (2002). HDL and arteriosclerosis: beyond reverse cholesterol transport. Atherosclerosis. v. 161, n. 1, p. 1-16.

Paavola, L.G. et al. (1985). Uptake of gold- and [3H]cholesteryl linoleate-labeled human low density lipoprotein by cultured rat granulosa cells: cellular mechanisms involved in lipoprotein metabolism and their importance to steroidogenesis. J Cell Biol. apr;100(4):1235-47.

Premoli, A.C. G. et al. (2000). Perfil lipídico em pacientes portadoras da síndrome dos ovários policísticos. Revista brasileira de ginecologia e obstetricia. v. 22, n. 2, p. 89-94.

Santos, I. S. et al. (2017). Insulin resistance is associated with carotid intima-media thickness in non-diabetic subjects. A cross-sectional analysis of the ELSA-Brasil cohort baseline. Atherosclerosis. v. 260, p. 34-40.

Sarto, D. A. Q. S. et al. (2018). Dry Extract of Passiflora incarnata L. leaves as a Cardiac and Hepatic Oxidative Stress Protector in LDLr-/- Mice Fed High-Fat Diet. v.61.

Shoelson, S.E., Herrero, L. & Naaz, A. (2007). Obesity, inflammation, and insulin resistance. Gastroenterology. v. 132, n. 6, p. 2169-2180.

Simpson, E. R. et al. (1980). Plasma lipoproteins in follicular fluid of human ovaries. The Journal of Clinical Endocrinology & Metabolism. v. 51, n. 6, p. 1469-1471.

Sirotkin, A. V. et al. (1998). Effect of follicular cells, IGF-I and tyrosine kinase blockers on oocyte maturation. Animal reproduction science. v. 51, n. 4, p. 333-344.

Souza, C. T. (2018). Envolvimento da inflamação subclínica e do estresse oxidativo na resistência à insulina associada a obesidade. HU rev. p. 211-220, 2018.

Tian, J. et al. (2006). Hyperlipidemia is a major determinant of neointimal formation in LDL receptor-deficient mice. Biochemical and biophysical research communications. v. 345, n. 3, p. 1004-1009.

Tomofuji, T. et al. (2006). Oxidative damage of periodontal tissue in the rat periodontitis model: effects of a high-cholesterol diet. FEBS letters. v. 580, n. 15, p. 3601-3604.

Van Den Hurk, R. & Zhao, J. (2005). Formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles. Theriogenology. v. 63, n. 6, p. 1717-1751.

Von- Eckardstein, A. & Assmann, G. (2000). Prevention of coronary heart disease by raising high-density lipoprotein cholesterol?. Current opinion in lipidology. v. 11, n. 6, p. 627-63.

Wensveen, F. M. et al. (2015). Interactions between adipose tissue and the immune system in health and malnutrition. In: Seminars in immunology. Academic Press, p. 322-333.

Yamasaki, M. et al. (2018). Vaccinium ashei leaves extract alleviates insulin resistance via AMPK independent pathway in C2C12 myotube model. Biochemistry and biophysics reports. v. 14, p. 182-187, 2018.

Yokode, M. et al. (1990). Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors. Science. v. 250, n. 4985, p. 1273-1275.

Aleisa, A. M., et al. (2013). Ameliorative effects of rutin and ascorbic acid combination on hypercholesterolemia-induced hepatotoxicity in female rats. African Journal of Pharmacy and Pharmacology. v. 7, n. 6, p. 280-288.

Alsheikh-ali, A. A., Kuvin, J. T. & Karas, R. H. (2005). High-density lipoprotein cholesterol in the cardiovascular equation: does the “good” still count?. Atherosclerosis. v. 180, n. 2, p. 217-223.

Andersen, J. M. & Dietschy, J. M. (1978). Relative importance of high and low density lipoproteins in the regulation of cholesterol synthesis in the adrenal gland, ovary, and testis of the rat. Journal of Biological Chemistry. v. 253, n. 24, p. 9024-9032.

Archuleta, T. L., et al. (2009). Oxidant stress-induced loss of IRS-1 and IRS-2 proteins in rat skeletal muscle: role of p38 MAPK. Free Radical Biology and Medicine. v. 47, n. 10, p. 1486-1493.

Argov, N. & Sklan, D. (2004). Expression of mRNA of Lipoprotein Receptor Related Protein 8, Low Density Lipoprotein Receptor, and Very Low Density Lipoprotein Receptor in Bovine Ovarian Cells During Follicular Development and Corpus Luteum Formation and Regression. Molecular Reproduction And Development. v. 68, p.169–175.

Assmann, G., Gotto Jr & Antonio M. (2004). HDL cholesterol and protective factors in atherosclerosis. Circulation. v. 109, n. 23_suppl_1, p. III-8-III-14.

Azhar, S., Leers-Sucheta, S. & Reaven, E. (2003). Cholesterol uptake in adrenal and gonadal tissues: the SR-BI and ‘selective’pathway connection. Front Biosci. v. 8, p. s998-1029.

Bhatia, B. & Price, C. A. (2001). Insulin alters the effects of follicle stimulating hormone on aromatase in bovine granulosa cells in vitro. Steroids. v. 66, n. 6, p. 511-519.

Brantmeier, S. A.; Grummer, R. R. & Ax, R. L. (1987). Concentrations of high density lipoproteins vary among follicular sizes in the bovine. Journal of dairy science. v. 70, n. 10, p. 2145-2149.

Breslow, J. L. (1993). Transgenic mouse models of lipoprotein metabolism and atherosclerosis. National Academy of Sciences. v. 90, n. 18, p. 8314-8318.

Carmeliet, P., Moons, L. & Collen, D. (1998). Mouse models of angiogenesis, arterial stenosis, atherosclerosis and hemostasis. Cardiovascular research. v. 39, n. 1, p. 8-33,

Chapman, M. J. (2004). Are the effects of statins on HDL-cholesterol clinically relevant?. European Heart Journal Supplements. v. 6, n. suppl_C, p. C58-C63.

Chaves, R. N., et al. (2011). Implicações da insulina na função ovariana e desenvolvimento embrionário. Acta Veterinaria Brasilica. v. 5, n. 2, p. 136-146.

Christison, J. et al. (1996). Rapid reduction and removal of HDL-but not LDL-associated cholesteryl ester hydroperoxides by rat liver perfused in situ. Biochemical Journal, v. 314, n. 3, p. 739-742.

Dandona, P. et al. (2013). Insulin infusion suppresses while glucose infusion induces toll like receptors and high mobility group-B1 protein expression in mononuclear cells of type 1 diabetics. American Journal of Physiology – Endocrinology and Metabolism. v. 304, p. E810 – E818.

Diamanti-kandarakis, E. & Dunaif, A. (2012). Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocrine reviews. v. 33, n. 6, p. 981-1030.

Dyer, C. A. & Curtiss, L. K. (1988). Apoprotein E-rich high density lipoproteins inhibit ovarian androgen synthesis. J Biol Chem. v. 263, n. 22, p. 10965–10973.

Egnatchik, R. A. et al. (2014). Palmitate-induced activation of mitochondrial metabolism promotes oxidative stress and apoptosis in H4IIEC3 rat hepatocytes. Metabolism. v. 63, n. 2, p. 283-295.

Fazio, S.& Linton, M. F. (2001). Mouse models of hyperlipidemia and atherosclerosis. Frontiers in bioscience: a journal and virtual library. v. 6, p. D515-25.

Friedewald, W.T., Levy, R. I. & Fredrickson, D. S. (1972). Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical chemistry. v. 18, n. 6, p. 499-502.

Garcia, J. A. D. et al. (2011). Efeito anti-inflamatório da lipoproteína de alta densidade no sistema cardiovascular de camundongos hiperlipidêmicos (Antiinflammatory effect of high density lipoprotein on the cardiovascular system of hyperlipidemic mice). Rev Port Cardiol. v. 30, n. 10, p. 763–769.

Garcia, J. A.D. et al. (2008). S-nitroso-n-acetylcysteine (SNAC) prevents myocardial alterations in hypercholesterolemic LDL receptor knockout mice by antiinflammatory action. Journal of cardiovascular pharmacology. v. 51, n. 1, p. 78-85, 2008.

Guo, T. et al. (2015). Low-density lipoprotein receptor affects the fertility of female mice. Reproduction, Fertility and Development. v. 27, n. 8, p. 1222-1232.

Hedrick, C. C. et al. (2001). In vivo interactions of apoA-II, apoA-I, and hepatic lipase contributing to HDL structure and antiatherogenic functions. Journal of lipid research. v. 42, n. 4, p. 563-570.

Henderson, K. M., Gorban, A. M. S & Boyd, G. S. (1981). Effect of LH factors regulating ovarian cholesterol metabolism and progesterone synthesis in PMSG-primed immature rats. Reproduction. v. 61, n. 2, p. 373-380.

Henriksen, E.J., Diamond-Stanic, Maggie K. & Marchionne, E. M. (2011). Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radical Biology and Medicine. v. 51, n. 5, p. 993-999.

Hwang, J. & Menon, K. M. (1983). Characterization of low density and high density lipoprotein receptors in the rat corpus luteum and regulation by gonadotropin. Journal of Biological Chemistry. v. 258, n. 13, p. 8020-8027.

Ishibashi, S. et al. (1993). Hypercholesterolemia in Low Density Lipoprotein Receptor Knockout Mice and its Reversal by Adenovirus-mediated Gene Delivery. The Journal of Clinical Investigation. v.92, p. 883-893.

Ishibashi, S. et al. (1994). The two-receptor model of lipoprotein clearance: tests of the hypothesis in" knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proceedings of the National Academy of Sciences. v. 91, n. 10, p. 4431-4435.

Lima, J. C. C. et al. (2000). Usando proteína C reativa de alta sensibilidade (PCR-AS) como preditor de doença cardiovascular. Newslab. v. 41, p. 164-166,

Louhio, H. et al. (2000). The effects of insulin, and insulin-like growth factors I and II on human ovarian follicles in long-term culture. Molecular human reproduction. v. 6, n. 8, p. 694-698.

Martins, A. M. et al. (2020). Grape juice attenuates left ventricular hypertrophy in dyslipidemic mice. Plos one. v. 15, n. 9, p. e0238163.

Miettinen, H. E. Rayburn, H. & Krieger M. (2001). Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)-deficient mice. J Clin Invest. 108(11):1717-22.

Miller, W. L.; Auchus, R. J. (2011). The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Ver. v. 32, p. 81–151.

Myers, M. G. et al. (1991). The insulin receptor functions normally in Chinese hamster ovary cells after truncation of the C terminus. Journal of Biological Chemistry. v. 266, n. 16, p. 10616-10623.

Nofer, J. R. et al. (2002). HDL and arteriosclerosis: beyond reverse cholesterol transport. Atherosclerosis. v. 161, n. 1, p. 1-16.

Paavola, L.G. et al. (1985). Uptake of gold- and [3H]cholesteryl linoleate-labeled human low density lipoprotein by cultured rat granulosa cells: cellular mechanisms involved in lipoprotein metabolism and their importance to steroidogenesis. J Cell Biol. apr;100(4):1235-47.

Premoli, A.C. G. et al. (2000). Perfil lipídico em pacientes portadoras da síndrome dos ovários policísticos. Revista brasileira de ginecologia e obstetricia. v. 22, n. 2, p. 89-94.

Santos, I. S. et al. (2017). Insulin resistance is associated with carotid intima-media thickness in non-diabetic subjects. A cross-sectional analysis of the ELSA-Brasil cohort baseline. Atherosclerosis. v. 260, p. 34-40.

Sarto, D. A. Q. S. et al. (2018). Dry Extract of Passiflora incarnata L. leaves as a Cardiac and Hepatic Oxidative Stress Protector in LDLr-/- Mice Fed High-Fat Diet. v.61.

Shoelson, S.E., Herrero, L. & Naaz, A. (2007). Obesity, inflammation, and insulin resistance. Gastroenterology. v. 132, n. 6, p. 2169-2180.

Simpson, E. R. et al. (1980). Plasma lipoproteins in follicular fluid of human ovaries. The Journal of Clinical Endocrinology & Metabolism. v. 51, n. 6, p. 1469-1471.

Sirotkin, A. V. et al. (1998). Effect of follicular cells, IGF-I and tyrosine kinase blockers on oocyte maturation. Animal reproduction science. v. 51, n. 4, p. 333-344.

Souza, C. T. (2018). Envolvimento da inflamação subclínica e do estresse oxidativo na resistência à insulina associada a obesidade. HU rev. p. 211-220, 2018.

Tian, J. et al. (2006). Hyperlipidemia is a major determinant of neointimal formation in LDL receptor-deficient mice. Biochemical and biophysical research communications. v. 345, n. 3, p. 1004-1009.

Tomofuji, T. et al. (2006). Oxidative damage of periodontal tissue in the rat periodontitis model: effects of a high-cholesterol diet. FEBS letters. v. 580, n. 15, p. 3601-3604.

Van Den Hurk, R. & Zhao, J. (2005). Formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles. Theriogenology. v. 63, n. 6, p. 1717-1751.

Von- Eckardstein, A. & Assmann, G. (2000). Prevention of coronary heart disease by raising high-density lipoprotein cholesterol?. Current opinion in lipidology. v. 11, n. 6, p. 627-63.

Wensveen, F. M. et al. (2015). Interactions between adipose tissue and the immune system in health and malnutrition. In: Seminars in immunology. Academic Press, p. 322-333.

Yamasaki, M. et al. (2018). Vaccinium ashei leaves extract alleviates insulin resistance via AMPK independent pathway in C2C12 myotube model. Biochemistry and biophysics reports. v. 14, p. 182-187, 2018.

Yokode, M. et al. (1990). Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors. Science. v. 250, n. 4985, p. 1273-1275.

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12/10/2021

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ABREU, J. M. .; SANTOS, G. B. .; CARVALHO, M. das G. de S.; MENCARELLI, J. M. .; CÂNDIDO, B. R. M. .; PRADO, B. B. de P. .; CAIXETA, E. S.; PEREIRA NETO , S. O. .; CORSETTI, . P. P. .; OLIVEIRA, N. de M. S. .; GARCIA, E. K. I. .; SILVÉRIO, A. C. P. .; ANJOS, J. A. dos .; ALVES , L. R. de C. .; GARCIA , J. A. D. . Dyslipidemia’s influence on the secretion ovarian’s steroids in female mice . Research, Society and Development, [S. l.], v. 10, n. 13, p. e298101321369, 2021. DOI: 10.33448/rsd-v10i13.21369. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/21369. Acesso em: 8 dec. 2021.

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Health Sciences