Maternal caffeine administration leads to adverse effects on adult mice offspring
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This study aimed to evaluate the role of caffeine chronic administration during gestation of C57BL/6 mice on cardiac remodeling and the expression of components of the renin-angiotensin system (RAS) in male offspring as adults.
Pregnant C57BL/6 female mice were divided into two groups (n = 10): Control group (C), dams were injected with the vehicle only (saline 0.9 % NaCl); Caffeine group (CF), dams received daily a subcutaneous injection of 20 mg/kg of caffeine/day (1 mg/mL saline). Pups had free access to standard chow since weaning to 3 months of age, when they were killed.
CF group showed increased energy expenditure (+7 %) with consequent reduction in body mass (BM) gain (−18 %), increased blood pressure (+48 %), and higher heart rate (+10 %) than C group. The ratio between LV mass/BM was greater (+10 %), with bigger cardiomyocytes (+40 %), and reduced vascularization (−25 %) in CF group than in C group. In the LV, the expression of angiotensin-converting enzyme (+30 %), Angiotensin II (AngII) (+60 %), AngII receptor (ATR)-1 (+77 %) were higher, and the expression of ATR-2 was lower (−46 %; P < 0.05) in CF group than in C group. In the kidney, the expressions of renin (+128 %) and ATR-1 (+88 %) were higher in CF group than in C group.
Chronic administration of caffeine to pregnant dams led to persistent activation of local RAS in the kidney and heart of the offspring, which, in turn, leads to high BP and adverse cardiac remodeling. These findings highlight the urge to encourage pregnant women to avoid food or medicines containing caffeine.
KeywordsCaffeine Fetal programming Energy expenditure Cardiac hypertrophy Renin-angiotensin system Hypertension
The authors are grateful to Aline Penna and Thatiany Marinho for their technical assistance. This study was supported by the Brazilian agencies FAPERJ (Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro, www.faperj.br) grant number (E-26/111.456/2011); and CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, www.cnpq.br) grant number (151781/2008 7); and CAPES (Coordenação de Aperfeiçoamento de Pessoa de Nível Superior).
Conflict of interest
The authors declare that there are no conflicts of interest.
- 3.Greenwood DC, Alwan N, Boylan S, Cade JE, Charvill J, Chipps KC, Cooke MS, Dolby VA, Hay AW, Kassam S, Kirk SF, Konje JC, Potdar N, Shires S, Simpson N, Taub N, Thomas JD, Walker J, White KL, Wild CP (2010) Caffeine intake during pregnancy, late miscarriage and stillbirth. Eur J Epidemiol 25:275–280CrossRefGoogle Scholar
- 4.Kirkinen P, Jouppila P, Koivula A, Vuori J, Puukka M (1983) The effect of caffeine on placental and fetal blood flow in human pregnancy. Am J Obstet Gynecol 147:939–942Google Scholar
- 7.Soyka LF (1979) Effects of methylxanthines on the fetus. Clin Perinatol 6:37–51Google Scholar
- 9.Riksen NP, Smits P, Rongen GA (2011) The cardiovascular effects of methylxanthines. Handb Exp Pharmacol: 413–437Google Scholar
- 12.Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123:1939–1951Google Scholar
- 13.Fischbeck KL, Rasmussen KM (1987) Effect of repeated reproductive cycles on maternal nutritional status, lactational performance and litter growth in ad libitum-fed and chronically food-restricted rats. J Nutr 117:1967–1975Google Scholar
- 17.Baquedano E, Garcia-Caceres C, Diz-Chaves Y, Lagunas N, Calmarza-Font I, Azcoitia I, Garcia-Segura LM, Argente J, Chowen JA, Frago LM (2011) Prenatal stress induces long-term effects in cell turnover in the hippocampus-hypothalamus-pituitary axis in adult male rats. PLoS ONE 6:e27549CrossRefGoogle Scholar
- 18.Liu Y, Xu D, Feng J, Kou H, Liang G, Yu H, He X, Zhang B, Chen L, Magdalou J, Wang H (2012) Fetal rat metabonome alteration by prenatal caffeine ingestion probably due to the increased circulatory glucocorticoid level and altered peripheral glucose and lipid metabolic pathways. Toxicol Appl Pharmacol 262:205–216CrossRefGoogle Scholar
- 19.Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133Google Scholar
- 22.Sheffield LG (1991) Caffeine administered during pregnancy augments subsequent lactation in mice. J Anim Sci 69:1128–1132Google Scholar
- 32.Kupfahl C, Pink D, Friedrich K, Zurbrugg HR, Neuss M, Warnecke C, Fielitz J, Graf K, Fleck E, Regitz-Zagrosek V (2000) Angiotensin II directly increases transforming growth factor beta1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res 46:463–475CrossRefGoogle Scholar
- 33.Osswald H, Schnermann J (2011) Methylxanthines and the kidney. Handb Exp Pharmacol 200:391–412Google Scholar
- 34.Butcher RW, Sutherland EW (1962) Adenosine 3′,5′-phosphate in biological materials. I. Purification and properties of cyclic 3′,5′-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3′,5′-phosphate in human urine. J Biol Chem 237:1244–1250Google Scholar
- 36.Brown R, Ollerstam A, Johansson B, Skott O, Gebre-Medhin S, Fredholm B, Persson AE (2001) Abolished tubuloglomerular feedback and increased plasma renin in adenosine A1 receptor-deficient mice. Am J Physiol Regul Integr Comp Physiol 281:R1362–R1367Google Scholar
- 37.Tofovic SP, Branch KR, Oliver RD, Magee WD, Jackson EK (1991) Caffeine potentiates vasodilator-induced renin release. J Pharmacol Exp Ther 256:850–860Google Scholar
- 42.Lumbers ER, Stevens AD (1987) The effects of frusemide, saralasin and hypotension on fetal plasma renin activity and on fetal renal function. J Physiol 393:479–490Google Scholar
- 46.Lassegue B, Alexander RW, Nickenig G, Clark M, Murphy TJ, Griendling KK (1995) Angiotensin II down-regulates the vascular smooth muscle AT1 receptor by transcriptional and post-transcriptional mechanisms: evidence for homologous and heterologous regulation. Mol Pharmacol 48:601–609Google Scholar
- 47.Torres ST, Silva GD, Aguila MB, Carvalho JJ, Mandarim-de-Lacerda CA (2008) Effects of rosiglitazone (a peroxysome proliferator-activated receptor gamma agonist) on the blood pressure and aortic structure in metabolically programmed (perinatal low protein) rats. Hypertens Res 31:965–975CrossRefGoogle Scholar
- 50.Ardaillou R (1999) Angiotensin II receptors. J Am Soc Nephrol 10(Suppl 11):S30–S39Google Scholar
- 51.Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD (1993) Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 45:205–251Google Scholar