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      Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?

      Journal of Child Psychology and Psychiatry, and Allied Disciplines
      Affective Symptoms, physiopathology, psychology, Animals, Arousal, physiology, Attention Deficit Disorder with Hyperactivity, Child, Corticotropin-Releasing Hormone, metabolism, Female, Humans, Hydrocortisone, blood, Hypothalamo-Hypophyseal System, Infant, Newborn, Language Development Disorders, Learning Disorders, Pregnancy, Prenatal Exposure Delayed Effects, Primates, Receptors, Glucocorticoid, Receptors, Mineralocorticoid, Risk Factors, Social Environment, Stress, Psychological, complications

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          Abstract

          We review a significant body of evidence from independent prospective studies that if a mother is stressed while pregnant, her child is substantially more likely to have emotional or cognitive problems, including an increased risk of attentional deficit/hyperactivity, anxiety, and language delay. These findings are independent of effects due to maternal postnatal depression and anxiety. We still do not know what forms of anxiety or stress are most detrimental, but research suggests that the relationship with the partner can be important in this respect. The magnitude of these effects is clinically significant, as the attributable load of emotional/behavioral problems due to antenatal stress and/or anxiety is approximately 15%. Animal models suggest that activity of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and its hormonal end-product cortisol are involved in these effects in both mother and offspring. The fetal environment can be altered if stress in the mother changes her hormonal profile, and in humans, there is a strong correlation between maternal and fetal cortisol levels. However, many problems remain in understanding the mechanisms involved in this interaction. For example, maternal cortisol responses to stress decline over the course of pregnancy, and earlier in pregnancy, the link between maternal and fetal cortisol is less robust. It is possible that the effects of maternal anxiety and stress on the developing fetus and child are moderated by other factors such as a maternal diet (e.g., protein load). It is suggested that extra vigilance or anxiety, readily distracted attention, or a hyper-responsive HPA axis may have been adaptive in a stressful environment during evolution, but exists today at the cost of vulnerability to neurodevelopmental disorders.

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          Epigenetic programming by maternal behavior.

          Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
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            Affective Style and Affective Disorders: Perspectives from Affective Neuroscience

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              Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life.

              Stress responses in the adult rat are programmed early in life by maternal care and associated with epigenomic marking of the hippocampal exon 1(7) glucocorticoid receptor (GR) promoter. To examine whether such epigenetic programming is reversible in adult life, we centrally infused the adult offspring with the essential amino acid L-methionine, a precursor to S-adenosyl-methionine that serves as the donor of methyl groups for DNA methylation. Here we report that methionine infusion reverses the effect of maternal behavior on DNA methylation, nerve growth factor-inducible protein-A binding to the exon 1(7) promoter, GR expression, and hypothalamic-pituitary-adrenal and behavioral responses to stress, suggesting a causal relationship among epigenomic state, GR expression, and stress responses in the adult offspring. These results demonstrate that, despite the inherent stability of the epigenomic marks established early in life through behavioral programming, they are potentially reversible in the adult brain.
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