Maternal Thyroid Hormone Deficiency During Gestation and Lactation Alters Metabolic and Thyroid Programming of the Offspring in the Adult Stage

Abstract

Environmental stimuli during critical developmental stages establish long-term physiological and structural patterns that “program” health during adult life. Little is known about how alterations in hormonal supply might have consequences in metabolic and thyroid programming. This work aims to prove that alterations in the supply of thyroid hormones during gestation and lactation have long-term consequences in the metabolic and thyroid programming of the offspring. Female Wistar rats were divided into euthyroid, hypothyroid, and hypothyroid with 20 μg/day of s.c. thyroxine (T₄), replacement wet nurses. Rats were mating, and after birth, pups were grouped according to their wet nurses group. Milk quality of wet nurses was assessed on days 7, 14, and 21. Body mass gain and energy intake of the offspring were monitored for 28 weeks after weaning. At sacrifice, we extracted and weighed their thyroid gland and adipose reserves, and collected blood to measure its metabolic and thyroid profiles. Hypothyroid wet nurses presented a persistent low quality of milk, while both male and female hypothyroid offspring presented lower body mass gain, higher blood glucose, dyslipidemia, hyperinsulinemia, and hyperleptinemia, as well as lower total adipose reserves, but higher visceral reserve, diminished T₃ and T₄ concentrations, and lower weight of thyroid gland. Thyroxine replacement prevented all changes in both wet nurses and pups. We conclude that maternal thyroid hormone deficiency during congenital and lactation stages alters the metabolic and thyroid programming of the offspring, while the reestablishment of maternal thyroid status during critical periods of development can prevent these alterations.

Key words

thyroid hormone - congenital hypothyroidism - metabolic programming - thyroid programming - hormonal replacement

• References

• 1 Fernandez-Twinn DS, Ozanne SE. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. Physiol Behav 2006; 88: 234-243
• 2 Ramirez-Velez. In utero fetal programming and its impact on health in adulthood. Endocrinol Nutr 2014; 61: 47-51
• 3 Murray AJ. Oxygen delivery and fetal-placental growth : Beyond a question of supply and demand ?. Placenta 2012; 33: e16-e22
• 4 Bell AW, Ehrhardt RA. Regulation of placental nutrient transport and implications for fetal growth. 2002; 211-230
• 5 Fowden AL, Forhead AJ. Endocrine mechanisms of intrauterine programming. Reproduction 2004; 127: 515-526
• 6 Fowden AL. Intrauterine programming of physiological systems: Causes and consequences. Physiology 2006; 21: 29-37
• 7 Moura AS, Franco DS, Cruz HG. et al. Malnutrition during lactation as a metabolic imprinting factor inducing the feeding pattern of offspring rats when adults. The role of insulin and leptin. Brazilian J Med Biol Res 2002; 35: 617-622
• 8 Patel MS, Srinivasan M. Metabolic programming: Causes and consequences. J Biol Chem 2002; 277: 1629-1632
• 9 Barker DJP. The developmental origins of adult disease. J Am Coll Nutr 2004; 23: 588S-595S
• 10 Barker DJP. In utero programming of chronic disease. Clin Sci (Lond) 1998; 128: 115-128
• 11 Vaag AA, Grunnet LG, Arora GP. et al. The thrifty phenotype hypothesis revisited. Diabetologia 2012; 55: 2085-2088
• 12 Mzayek F, Cruickshank JK, Amoah D. et al. Birth weight was longitudinally associated with cardiometabolic risk markers in mid-adulthood. Ann Epidemiol 2016; 26: 643-647
• 13 Kalish JM, Jiang C, Bartolomei MS. Epigenetics and imprinting in human disease. Int J Dev Biol 2014; 58: 291-298
• 14 Huang B, Jiang C, Zhang R. Epigenetics: The language of the cell?. Epigenomics 2014; 6: 73-88
• 15 Lopez-Jaramillo P. Cardiometabolic disease in latin america: The role of fetal programming in response to maternal malnutrition. Rev Esp Cardiol 2009; 62: 670-676
• 16 Vuguin PM. Animal models for small for gestational age and fetal programing of adult disease. Horm Res 2007; 68: 113-123
• 17 Mayr J, Kohlfürst S, Gallowitsch H-J. et al. Thyroid and pregnancy. Wien Med Wochenschr 2010; 160: 186-193
• 18 Reid RE, Kim E, Page D. et al. Thyroxine replacement in an animal model of congenital hypothyroidism. Physiol Behav 2007; 91: 299-303
• 19 Shanholtz HJ. Congenital hypothyroidism. J Pediatr Nurs 2013; 28: 200-202
• 20 Pineda-Reynoso M, Cano-Europa E, Blas-Valdivia V. et al. Hypothyroidism during neonatal and perinatal period induced by thyroidectomy of the mother causes depressive-like behavior in prepubertal rats. Neuropsychiatr Dis Treat 2010; 6: 137-143
• 21 Haschke F, Grathwohl D, Haiden N. Metabolic programming: Effects of early nutrition on growth, metabolism and body composition. Nestle Nutr Inst Workshop Ser 2016; 86: 87-95
• 22 Moisiadis VG, Matthews SG. Glucocorticoids and fetal programming part 2: Mechanisms. Nat Rev Endocrinol 2014; 10: 403-411
• 23 Dos Santos E, Duval F. The roles of leptin and adiponectin at the fetal-maternal interface in humans. Horm Mol Biol Clin Investig 2015; 1: 47-63
• 24 Walsh JM, Byrne J, Mahony RM. et al. Early human development leptin , fetal growth and insulin resistance in non-diabetic pregnancies. Early Hum Dev 2014; 90: 271-274
• 25 Jones RH, Ozanne SE. Fetal programming of glucose-insulin metabolism. Mol Cell Endocrinol 2009; 297: 4-9
• 26 Hattersley AT, Tooke JE. The fetal insulin hypothesis: An alternative explanation of the association of low bir thweight with diabetes and vascular disease. Lancet 1999; 353: 1789-1792
• 27 Hendrich CE, Porterfield SP, Henderson J. et al. A comparison of the effects of altered thyroid and parathyroid function on reproduction in the rat. Horm Metab Res 1976; 8: 220-226
• 28 Hatsuta M, Abe K, Tamura K. et al. Effects of hypothyroidism on the estrous cycle and reproductive hormones. Eur J Pharmacol 2004; 486: 343-348
• 29 Hendrich CE, Jackson WJ, Porterfield SP. Behavioral testing of progenies of Tx (Hypothyroid) and growth Hormone-Treated Tx rats: An animal model for mental retardation. Neuroendocrinology 1984; 38: 429-437
• 30 Hapon MB, Simoncini M, Via G. et al. Effect of hypothyroidism on hormone profiles in virgin, pregnant and lactating rats, and on lactation. Reproduction 2003; 126: 371-382
• 31 Saran S, Gupta BS, Philip R. et al. Effect of hypothyroidism on female reproductive hormones. Indian J Endocrinol Metab 2016; 2-7
• 32 Hapon MB, Varas SM, Jahn GA. et al. Effects of hypothyroidism on mammary and liver lipid metabolism in virgin and late-pregnant rats. J Lipid Res 2005; 46: 1320-1330
• 33 Hapon MB, Varas SM, Giménez MS. et al. Reduction of mammary and liver lipogenesis and alteration of milk composition during lactation in rats by hypothyroidism. Thyroid 2007; 17: 11-18
• 34 Patel MS, Srinivasan M. Metabolic programming due to alterations in nutrition in the immediate postnatal period. J Nutr 2010; 3: 658-661
• 35 Ozcelik F, Yuksel C, Arslan E. et al. Relationship between visceral adipose tissue and adiponectin, inflammatory markers and thyroid hormones in obese males with hepatosteatosis and insulin resistance. Arch Med Res 2013; 44: 273-280
• 36 de Moura EG, Lisboa PC, Custódio CM. et al. Malnutrition during lactation changes growth hormone mRNA expression in offspring at weaning and in adulthood. J Nutr Biochem 2007; 18: 134-139
• 37 Papakonstantinou E, Lambadiari V, Dimitriadis G. et al. Metabolic syndrome and cardiometabolic risk factors. Curr Vasc Pharmacol 2013; 11: 858-879
• 38 Thompson JA, Regnault TRH. In utero origins of adult insulin resistance and vascular dysfunction. Semin Reprod Med 2011; 29: 211-224
• 39 Patel MS, Srinivasan M. Metabolic programming in the immediate postnatal life. Ann Nutr Metab 2011; 58 (Suppl. 02) 18-28
• 40 Ayala-Moreno R, Racotta R, Anguiano B. et al. Perinatal undernutrition programmes thyroid function in the adult rat offspring. Br J Nutr 2013; 110: 2207-2215
• 41 Andersen SL, Olsen J, Laurberg P. Foetal programming by maternal thyroid disease. Clin Endocrinol (Oxf) 2015; 83: 751-758
• 42 Blackburn S. Maternal-Fetal thyroid interactions. J Perinat Neonatal Nurs 2009; 23: 312-313
• 43 Calvo RM, Jauniaux E, Gulbis B. et al. Fetal Tissues are exposed to biologically relevant free thyroxine cncentrations during earlky phases of development. J Clin Endocrinol Metab 2002; 87: 1768-1777
• 44 Thorpe-Beeston JG, Nicolaides KH, Felton CV. et al. Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N Engl J Med 1991; 324: 532-536
• 45 Szinnai G. Genetics of normal and abnormal thyroid development in humans. Best Pract Res Clin Endocrinol Metab 2014; 28: 133-150
• 46 Calvo R, Obregón MJ, Ruiz de Oña C. et al. Congenital hypothyroidism, as studied in rats. Crucial role of maternal thyroxine but not of 3,5,3’-triiodothyronine in the protection of the fetal brain. J Clin Invest 1990; 86: 889-899