Background There is growing evidence that the intrauterine environment can impact the neurodevelopment of the fetus through alterations in the functional epigenome of the placenta. In the placenta, the HSD11B2 gene encoding the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol, is regulated by DNA methylation, and has been shown to be susceptible to stressors from the maternal environment. Methodology/Principal Findings We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 185 healthy newborn infants and infant and maternal characteristics, as well as the association between this epigenetic variability and newborn neurobehavioral outcome assessed with the NICU Network Neurobehavioral Scales. Controlling for confounders, HSD11B2 methylation extent is greatest in infants with the lowest birthweights (P = 0.04), and this increasing methylation was associated with reduced scores of quality of movement (P = 0.04). Conclusions/Significance These results suggest that factors in the intrauterine environment which contribute to birth outcome may be associated with placental methylation of the HSD11B2 gene and that this epigenetic alteration is in turn associated with a prospectively predictive early neurobehavioral outcome, suggesting in some part a mechanism for the developmental origins of infant neurological health.
References
[1]
Robins JC, Marsit CJ, Padbury JF, Sharma SS (2011) Endocrine disruptors, environmental oxygen, epigenetics and pregnancy. Frontiers in bioscience 3: 690–700.
[2]
Barker DJ, Osmond C (1988) Low birth weight and hypertension. BMJ 297: 134–135.
[3]
Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ (1989) Weight in infancy and death from ischaemic heart disease. Lancet 2: 577–580.
[4]
Barker D (1998) Babies and Health in Later Life. Edinburgh Churchhill Livingstone.
[5]
Cannon TD, Rosso IM (2002) Levels of analysis in etiological research on schizophrenia. Dev Psychopathol 14: 653–666.
[6]
Alati R, Lawlor DA, Mamun AA, Williams GM, Najman JM, et al. (2007) Is there a fetal origin of depression? Evidence from the Mater University Study of Pregnancy and its outcomes. Am J Epidemiol 165: 575–582.
[7]
Gale CR, Martyn CN (2004) Birth weight and later risk of depression in a national birth cohort. Br J Psychiatry 184: 28–33.
[8]
Thompson C, Syddall H, Rodin I, Osmond C, Barker D (2001) Birth weight and the risk of depressive disorder in late life. Br J Psychiatry 179: 450–455.
[9]
Cheung YB (2002) Early origins and adult correlates of psychosomatic distress. Soc Sci Med 55: 937–948.
[10]
Cheung YB, Khoo KS, Karlberg J, Machin D (2002) Association between psychological symptoms in adults and growth in early life: longitudinal follow up study. BMJ 325: 749.
[11]
Wiles NJ, Peters TJ, Leon DA, Lewis G (2005) Birth weight and psychological distress at age 45–51 years: results from the Aberdeen Children of the 1950s cohort study. Br J Psychiatry 187: 21–28.
[12]
Welberg LA, Seckl JR (2001) Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 13: 113–128.
[13]
Petraglia F, Coukos G, Volpe A, Genazzani AR, Vale W (1991) Involvement of placental neurohormones in human parturition. Ann N Y Acad Sci 622: 331–340.
[14]
Yen SS (1994) The placenta as the third brain. J Reprod Med 39: 277–280.
[15]
Yen SS (1991) Endocrine-metabolic adaptions in pregnancy. In: Yen SS, Jaffe RB, editors. Reproductive Endocrinology. 3rd ed. Philadelphia: WB Saunders. pp. 936–970.
[16]
Lester BM, Padbury JF (2009) Third pathophysiology of prenatal cocaine exposure. Dev Neurosci 31: 23–35.
[17]
Sarkar S, Tsai SW, Nguyen TT, Plevyak M, Padbury JF, et al. (2001) Inhibition of placental 11beta-hydroxysteroid dehydrogenase type 2 by catecholamines via alpha-adrenergic signaling. Am J Physiol Regul Integr Comp Physiol 281: R1966–1974.
Filiberto AC, Maccani MA, Koestler D, Wilhelm-Benartzi C, Avissar-Whiting M, et al. (2011) Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta. Epigenetics 6: 566–572.
Seckl JR, Holmes MC (2007) Mechanisms of disease: glucocorticoids, their placental metabolism and fetal ‘programming’ of adult pathophysiology. Nature clinical practice Endocrinology & metabolism 3: 479–488.
[22]
Welberg LA, Thrivikraman KV, Plotsky PM (2005) Chronic maternal stress inhibits the capacity to up-regulate placental 11beta-hydroxysteroid dehydrogenase type 2 activity. J Endocrinol 186: R7–R12.
[23]
Mairesse J, Lesage J, Breton C, Breant B, Hahn T, et al. (2007) Maternal stress alters endocrine function of the feto-placental unit in rats. Am J Physiol Endocrinol Metab 292: E1526–1533.
[24]
Glover V, Bergman K, Sarkar P, O'Connor TG (2009) Association between maternal and amniotic fluid cortisol is moderated by maternal anxiety. Psychoneuroendocrinology 34: 430–435.
[25]
Ponder KL, Salisbury A, McGonnigal B, Laliberte A, Lester B, et al. (2011) Maternal depression and anxiety are associated with altered gene expression in the human placenta without modification by antidepressant use: implications for fetal programming. Developmental psychobiology 53: 711–723.
[26]
Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CR (1993) Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 341: 339–341.
[27]
Murphy VE, Zakar T, Smith R, Giles WB, Gibson PG, et al. (2002) Reduced 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma. J Clin Endocrinol Metab 87: 1660–1668.
[28]
Shams M, Kilby MD, Somerset DA, Howie AJ, Gupta A, et al. (1998) 11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction. Hum Reprod 13: 799–804.
[29]
Talge NM, Neal C, Glover V (2007) Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? Journal of child psychology and psychiatry, and allied disciplines 48: 245–261.
[30]
Seckl JR, Meaney MJ (2004) Glucocorticoid programming. Annals of the New York Academy of Sciences 1032: 63–84.
[31]
Ellman LM, Schetter CD, Hobel CJ, Chicz-Demet A, Glynn LM, et al. (2008) Timing of fetal exposure to stress hormones: effects on newborn physical and neuromuscular maturation. Developmental psychobiology 50: 232–241.
[32]
Sandman CA, Davis EP, Buss C, Glynn LM (2011) Prenatal programming of human neurological function. International journal of peptides. 2011. 837596 p.
[33]
Welberg LA, Seckl JR, Holmes MC (2000) Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. Eur J Neurosci 12: 1047–1054.
[34]
Holmes MC, Sangra M, French KL, Whittle IR, Paterson J, et al. (2006) 11beta-Hydroxysteroid dehydrogenase type 2 protects the neonatal cerebellum from deleterious effects of glucocorticoids. Neuroscience 137: 865–873.
[35]
Lucassen PJ, Bosch OJ, Jousma E, Kromer SA, Andrew R, et al. (2009) Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low, anxiety: possible key role of placental 11beta-hydroxysteroid dehydrogenase type 2. Eur J Neurosci 29: 97–103.
[36]
American Academy of Pediatrics CoFaN, and Canadian Paediatric Society, Fetus and Newborn Committee (2002) Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 109: 330–338.
[37]
Doyle LW, Ehrenkranz RA, Halliday HL (2010) Dexamethasone treatment after the first week of life for bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology 98: 289–296.
[38]
Stephens BE, Liu J, Lester B, Lagasse L, Shankaran S, et al. (2010) Neurobehavioral assessment predicts motor outcome in preterm infants. J Pediatr 156: 366–371.
[39]
El-Dib M, Massaro AN, Glass P, Aly H (2011) Neurobehavioral assessment as a predictor of neurodevelopmental outcome in preterm infants. J Perinatol.
[40]
Liu J, Bann C, Lester B, Tronick E, Das A, et al. (2010) Neonatal neurobehavior predicts medical and behavioral outcome. Pediatrics 125: e90–98.
[41]
Tronick EZ, Olson K, Rosenberg R, Bohne L, Lu J, et al. (2004) Normative neurobehavioral performance of healthy infants on the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Pediatrics 113: 676–678.
[42]
Shum D, Neulinger K, O'Callaghan M, Mohay H (2008) Attentional problems in children born very preterm or with extremely low birth weight at 7–9 years. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists 23: 103–112.
[43]
Fenton TR (2003) A new growth chart for preterm babies: Babson and Benda's chart updated with recent data and a new format. BMC Pediatr 3: 13.
[44]
Lester B, Tronick E (2004) The Neonatal Intensive Care Unit Network Neurobehavioral Scale. Pediatrics 113: 631–695.
