Short- and long-term reproductive effects of prenatal and lactational growth restriction caused by maternal diabetes in male rats

Reproductive Biology and Endocrinology

Wilma DG Kempinas¹  Gustavo T Volpato¹  Carla DB Fernandez¹  Raquel Spadotto¹  Juliana E Perobelli⁴  Débora C Damasceno²  Elaine MP Amorim³ 

[1] Department of Morphology, Institute of Biosciences, UNESP - Univ Estadual Paulista, 18618-970, Botucatu, São Paulo, Brazil;Department of Gynecology and Obstetrics, Botucatu Medical School, UNESP - Univ Estadual Paulista, Botucatu, São Paulo, Brazil;Center of Biological and Health Sciences (CCBS), State University of West Paraná (UNIOESTE), Cascavel, Paraná, Brazil;Graduate Program in Cell and Structural Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil

关键词: sexual development;    puberty;    maternal diabetes;    male rat;    growth restriction;    developmental programming;   

Others  :  1151299
DOI  :  10.1186/1477-7827-9-154

 received in 2011-08-12, accepted in 2011-12-06,  发布年份 2011

【 摘 要 】

Background

A suboptimal intrauterine environment may have a detrimental effect on gonadal development and thereby increases the risk for reproductive disorders and infertility in adult life. Here, we used uncontrolled maternal diabetes as a model to provoke pre- and perinatal growth restriction and evaluate the sexual development of rat male offspring.

Methods

Maternal diabetes was induced in the dams through administration of a single i.v. dose of 40 mg/kg streptozotocin, 7 days before mating. Female rats presenting glycemic levels above 200 mg/dL after the induction were selected for the experiment. The male offspring was analyzed at different phases of sexual development, i.e., peripuberty, postpuberty and adulthood.

Results

Body weight and blood glucose levels of pups, on the third postnatal day, were lower in the offspring of diabetic dams compared to controls. Maternal diabetes also provoked delayed testicular descent and preputial separation. In the offspring of diabetic dams the weight of reproductive organs at 40, 60 and 90 days-old was lower, as well as sperm reserves and sperm transit time through the epididymis. However the plasma testosterone levels were not different among experimental groups.

Conclusions

It is difficult to isolate the effects directly from diabetes and those from IUGR. Although the exposure to hyperglycemic environment during prenatal life and lactation delayed the onset of puberty in male rats, the IUGR, in the studied model, did not influenced the structural organization of the male gonads of the offspring at any point during sexual development. However the decrease in sperm reserves in epididymal cauda and the acceleration in sperm transit time in this portion of epididymis may lead to an impairment of sperm quality and fertility potential in these animals. Additional studies are needed in attempt to investigate the fertility of animals with intrauterine growth restriction by maternal diabetes and possible multigenerational effects.

【 授权许可】

   
2011 Amorim et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Bautista CJ, Boeck L, Larrea F, Nathanielsz PW, Zambrano E: Effects of a maternal low protein isocaloric diet on milk leptin and progeny serum leptin concentration and appetitive behavior in the first 21 days of neonatal life in the rat. Pediatr Res 2008, 63(4):358-363.
• [2]Ojeda NB, Grigore D, Alexander BT: Intrauterine growth restriction: fetal programming of hypertension and kidney disease. Adv Chronic Kidney Dis 2008, 15(2):101-106.
• [3]Eriksson JG, Forsén TJ, Kajantie E, Osmond C, Barker DJ: Childhood growth and hypertension in later life. Hypertension 2007, 49(6):1415-1421.
• [4]Thapar A, Harold G, Rice F, Ge X, Boivin J, Hay D, Van Den Bree M, Lewis A: Do intrauterine or genetic influences explain the foetal origins of chronic disease? A novel experimental method for disentangling effects. BMC Med Res Methodol 2007, 22:7-25.
• [5]Hng TM, Cheung NW, McLean M: Growth hormone and cortisol dynamic function in relation to birth weight: a study in adult twins. J Clin Endocrinol Metab 2005, 90(5):2781-2786.
• [6]Boloker J, Gertz SJ, Simmons RA: Gestational diabetes leads to the development of diabetes in adulthood in the rat. Diabetes 2002, 51(5):1499-1506.
• [7]Barker DJ, Clark PM: Fetal undernutrition and disease in later life. Rev Reprod 1997, 2(2):105-112.
• [8]Main KM, Jensen RB, Asklund C, Hoi-Hansen CE, Skakkebaek NE: Low birth weight and male reproductive function. Horm Res 2006, 65(3):116-122.
• [9]Ibáñez L, Ferrer A, Marcos MV, Hierro FR, de Zegher F: Early puberty: rapid progression and reduced final height in girls with low birth weight. Pediatrics 2000, 106(5):E72..
• [10]Ibáñez L, Jaramillo A, Enríquez G, Miró E, López-Bermejo A, Dunger D, de Zegher F: Polycystic ovaries after precocious pubarche: relation to prenatal growth. Hum Reprod 2007, 22(2):395-400.
• [11]van Weissenbruch MM: Premature adrenarche, polycystic ovary syndrome and intrauterine growth retardation: does a relationship exist? Curr Opin Endocrinol Diabetes Obes 2007, 14(1):35-40.
• [12]Guzmán C, Cabrera R, Cárdenas M, Larrea F, Nathanielsz PW, Zambrano E: Protein restriction during fetal and neonatal development in the rat alters. J Physiol 2006, 572(1):97-108.
• [13]Bruin JP, Dorland M, Bruinse HW, Spliet W, Nikkels PGJ, Te Velde ER: Fetal growth retardation as a cause of impaired ovarian development. Early Hum Dev 1998, 51(1):39-46.
• [14]Fujimoto T, Suwa T, Kabe K, Adachi T, Nakabayashi M, Amamiya T: Placental insufficiency in early gestation is associated with hypospadias. J Pediatr Surg 2008, 43(2):358-361.
• [15]Gatti JM, Kirsch AJ, Troyer WA, Perez-Brayfield MR, Smith EA, Scherz HC: Increased incidence of hypospadias in small-for-gestational age infants in a neonatal intensive-care unit. BJU Int 2001, 87(6):548-550.
• [16]Weir HK, Marrett LD, Kreiger N, Darlington GA, Sugar L: Pre-natal and peri-natal exposures and risk of testicular germ-cell cancer. Int J Cancer 2000, 87(3):438-443.
• [17]Zambrano E, Bautista CJ, Deás M, Martínez-Samayoa PM, González-Zamorano M, Ledesma H, Morales J, Larrea F, Nathanielsz PW: A low maternal protein diet during pregnancy and lactation has sex- and window of exposure-specific effects on offspring growth and food intake, glucose metabolism and serum leptin in the rat. J Physiol 2006, 571(1):221-230.
• [18]Zambrano E, Rodríguez-González GL, Guzmán C, García-Becerra R, Boeck L, Díaz L, Menjivar M, Larrea F, Nathanielsz PW: A maternal low protein diet during gestation and lactation in the rat male reproductive development. J Physiol 2005, 563(1):275-284.
• [19]Zambrano E, Martínez-Samayoa PM, Bautista CJ, Deás M, Guillén L, Rodríguez-González GL, Guzmán C, Larrea F, Nathanielsz PW: Sex differences in transgenerational alterations of growth and metabolism in progeny (F2) of female offspring (F1) of rats fed a low protein diet during gestation and lactation. J Physiol 2005, 566(1):225-236.
• [20]Garofano A, Czernichow P, Bréant B: In utero undernutrition impairs rat beta-cell development. Diabetologia 1997, 40(10):1231-1234.
• [21]Simmons RA, Templeton LJ, Gertz SJ: Intrauterine growth retardation leads to the development of type 2 diabetes in rat. Diabetes 2001, 50(10):2279-2286.
• [22]Engelbregt MJ, Houdijk ME, Popp-Snijders C, Delemarre-van de Waal HA: The effects of intrauterine growth retardation and postnatal undernutrition on onset of puberty in male and female rats. Pediatr Res 2000, 48(6):803-807.
• [23]Lesage J, Del-Favero F, Leonhardt M, Louvart H, Maccari S, Vieau D, Darnaudery M: Prenatal stress induces intrauterine growth restriction and programmes glucose intolerance and feeding behaviour disturbances in the aged rat. J Endocrinol 2004, 181(2):291-296.
• [24]Neitzke U, Harder T, Schellong K, Melchior K, Ziska T, Rodekamp E, Dudenhausen JW, Plagemann A: Intrauterine growth restriction in a rodent model and developmental programming of the metabolic syndrome: a critical appraisal of the experimental evidence. Placenta 2008, 29(3):246-254.
• [25]Holemans K, Van Bree R, Verhaeghe J, Meurrens K, Van Assche FA: Maternal semistarvation and streptozotocin-diabetes in rats have different effects on the vivo glucose uptake by peripheral tissues in their female adult offspring. J Nutr 1997, 127(7):1371-1376.
• [26]Holemans K, Gerber RT, Meurrens K, De Clerck F, Poston L, Van Assche FA: Streptozotocin diabetes in the pregnant induces cardiovascular dysfunction in adult offspring. Diabetologia 1999, 42(1):81-89.
• [27]Holemans K, Aerts L, Van Assche FA: Fetal Growth restriction and consequences for the offspring in animal models. J Soc Gynecol Investig 2003, 10(7):392-399.
• [28]Chahoud I, Paumgartten FJ: Influence of litter size on the postnatal growth of rat pups: Is there a rationale for litter-size standardization in toxicity studies? Environ Res 2009, 109(8):1021-1027.
• [29]Robb GW, Amman RP, Killian GJ: Daily sperm production and epididymal sperm reserves of pubertal and adult rats. J Reprod Fertil 1978, 54(1):103-107.
• [30]Fernandes GS, Arena AC, Fernandez CD, Mercadante A, Barbisan LF, Kempinas WG: Reproductive effects in male rats exposed to diuron. Reprod Toxicol 2007, 23(1):106-112.
• [31]Carvalho TL, Guimaraes MA, Kempinas WG, Petenusci SO, Rosa e Silva AA: Effects of guanethidine-induced sympathectomy on the spermatogenic and steroidogenic testicular functions of pre-pubertal to mature rats. Andrologia 1996, 28(2):117-122.
• [32]Ferreira AL, Lison L, Valeri V: Caryometric study of spermatogenesis in the rat. Z Zellforsch Mikrosk Anat 1967, 76(1):31-55.
• [33]Leblond CP, Clermont Y: Definition of the stages of the cycle of the seminiferous epithelium in the rat. Ann N Y Acad Sci 1952, 55(4):548-573.
• [34]Al Ghafli MH, Padmanabhan R, Kataya HH, Berg B: Effects of α-lipoid acid supplementation on maternal diabetes-induced growth retardation and congenital anomalies in rat fetuses. Mol Cell Biochem 2004, 261(1-2):123-135.
• [35]Damasceno DC, Volpato GT, de Mattos Paranhos Calderon I, Cunha Rudge MV: Oxidative stress and diabetes in gestation rats. Anim Reprod Sci 2002, 72(3-4):235-244.
• [36]Padmanabhan R, Al-Zuhair AG: Congenital malformations and intrauterine growth retardation in streptozotocin induced diabetes during gestation in rat. Reprod Toxicol 1998, 1(2):117-125.
• [37]Holemans K, Aerts L, Van Assche FA: Lifetime consequences of abnormal fetal pancreatic development. J Physiol 2003, 547(1):11-20.
• [38]Van Assche FA, Holemans K, Aerts L: Long-term consequences for offspring of diabetes during gestation. Br Med Bull 2001, 60:173-182.
• [39]Han J, Xu J, Long YS, Epstein PN, Liu YQ: Rat maternal diabetes impairs pancreatic beta-cell function in the offspring. Am J Physiol Endocrinol Metab 2007, 293(1):E228-236.
• [40]Kobayashi A, Ueda Y, Morikawa H, Mochizuki M: Effects of maternal hyperglycemia on fetal growing mechanism. Nihon Sanka Fujinka Gakkai Zasshi 1991, 43(3):289-296.
• [41]Fahrenkrog S, Harder T, Stolaczyk E, Melchior K, Franke K, Dudenhausen JW, Plagemann A: Cross-fostering to diabetic rat dams affects early development of mediobasal hypothalamic nuclei regulating food intake, body weight, and metabolism. J Nutr 2004, 134(3):648-654.
• [42]Lau C, Sullivan MK, Hazelwood RL: Effects of diabetes mellitus on lactation in the rat. Proc Soc Exp Biol Med 1993, 204(1):81-89.
• [43]Neubauer SH: Lactation in insulin-dependent diabetes. Prog Food Nutr Sci 1990, 14(4):333-370.
• [44]Léonhardt M, Lesage J, Croix D, Dutriez-Casteloot I, Beauvillain JC, Dupouy JP: Effects of perinatal maternal food restriction on pituitary-gonadal axis and plasma leptin levels in rat pup at birth and weaning and on timing of puberty. Biol Reprod 2003, 68(2):390-400.
• [45]Engelbregt MJ, Van Weissenbrunch MM, Popp-Snijders C, Lips P, Delemarre-van de Waal HA: Body mass index, body composition, and leptin at onset of puberty in male and female rats after intrauterine growth retardation and after early postnatal food nutrition. Pediatr Res 2001, 50(4):474-478.
• [46]Canavan JP, Holt J, Goldspink DF: The effects of established diabetes on the growth of the fetal liver and skin in the rat. Comp Biochem Physiol Comp Physiol 1992, 102(3):547-552.
• [47]Amri K, Freund N, Vilar J, Merlet-Bénichou C, Lelièvre-Pégorier M: Adverse effects of hyperglycaemia on kidney development in rats: in vivo and in vitro studies. Diabetes 1999, 48(11):2240-2245.
• [48]Bourbon JR, Pignol B, Marin L, Rieutort M, Tordet C: Maturation of fetal rat lung in diabetic pregnancies of graduated severity. Diabetes 1985, 34(8):734-743.
• [49]Toledo FC, Perobelli JE, Pedrosa FP, Anselmo-Franci JÁ, Kempinas WD: In utero protein restriction causes growth delay and alters sperm parameters in adult male rats. Reprod Biol Endocrinol 2011, 9:94. BioMed Central Full Text
• [50]Sujarit S, Pholpramool C: Enhancement of sperm transport through the rat epididymis after castration. J Reprod Fertil 1985, 74(2):497-502.
• [51]Ricker DD, Crone JK, Chamness SL, Klinefelter GR, Chang TS: Partial sympathetic denervation of the rat epididymis permits fertilization but inhibits embryo development. J Androl 1997, 18(2):131-138.
• [52]Cooper TG: Epididymis. In Encyclopedia of Reproduction. Volume 2. Edited by Knobil E, Neill JD. California: Academic Press; 1998::1-17.
• [53]Persson I, Ahlsson F, Ewald U, Tuvemo T, Qingyuan M, von Rosen D, Proos L: Influence of perinatal factors on the onset of puberty in boys and girls: implications for interpretation of link with risk of long term diseases. Am J Epidemiol 1999, 150(7):747-755.
• [54]Bhargava SK, Ramji S, Srivastava U, Sachdev HP, Kapani V, Datta V, Satyanarayana L: Growth and sexual maturation of low birth weight children: a 14 year follow up. Indian Pediatr 1995, 32(9):963-970.
• [55]White SL, Perkovic V, Cass A, Chang CL, Poulter NR, Spector T, Haysom L, Craig JC, Salmi IA, Chadban SJ, Huxley RR: Is low birth weights an antecedent of CDK in latter life? A systematic rewiew of observational studies. Am J Kidney Dis 2009, 54:248-261.
• [56]Lim K, Lombardo P, Schneider-Kolsky M, Hilliard L, Denton KM, Black MJ: Induction of hyperglycemia in adult intrauterine growth-restricted rats: effects on renal function. Am J Physiol Renal Physiol 2011, 301(2):F288-F294.
• [57]Rodríguez CM, Kirby JL, Hinton BT: The development of the epididymis. In The Epididymis - from molecules to clinical practice. 1st edition. Edited by Robaire B, Hinton BT. New York: Kluwer Academic/Plenum Publisher; 2002:251-268.
• [58]Petry CJ, Desai M, Ozanne SE, Hales CN: Early and late nutritional windows for diabetes susceptibility. Proc Nutr Soc 1997, 56:233-242.
• [59]Burdge GC, Slater-Jefferies J, Torrens C, Phillips ES, Hanson MA, Lillycrop KA: Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 2007, 97(3):435-439.