Sex-Specific Programming of Offspring Emotionality after Stress Early in Pregnancy

By Bridget R. Mueller, T. Bale. Journal of Neuroscience, 2008

1,009 citations recorded by the source corpus.

Prenatal stress is associated with an increased vulnerability to neurodevelopmental disorders, including autism and schizophrenia. To determine the critical time window when fetal antecedents may induce a disease predisposition, we examined behavioral responses in offspring exposed to stress during early, mid, and late gestation. We found that male offspring exposed to stress early in gestation displayed maladaptive behavioral stress responsivity, anhedonia, and an increased sensitivity to selective serotonin reuptake inhibitor treatment. Long-term alterations in central corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, as well as increased hypothalamic–pituitary–adrenal (HPA) axis responsivity, were present in these mice and likely contributed to an elevated stress sensitivity. Changes in CRF and GR gene methylation correlated with altered gene expression, providing important evidence of epigenetic programming during early prenatal stress. In addition, we found the core mechanism underlying male vulnerability may involve sex-specific placenta responsivity, where stress early in pregnancy significantly increased expression of PPARα (peroxisome proliferator-activated receptor α), IGFBP-1 (insulin-like growth factor binding protein 1), HIF3α (hypoxia-inducible factor 3a), and GLUT4 (glucose transporter 4) in male placentas but not females. Examination of placental epigenetic machinery revealed basal sex differences, providing further evidence that sex-specific programming begins very early in pregnancy, and may contribute to the timing and vulnerability of the developing fetus to maternal perturbations. Overall, these results indicate that stress experience early in pregnancy may contribute to male neurodevelopmental disorders through impacts on placental function and fetal development.

Subfields: Pediatrics, Perinatology and Child Health, Public Health, Environmental and Occupational Health, Social Psychology

View Paper: https://www.semanticscholar.org/paper/2854fd3727de5ddf0442bc8f1b24c1a3749dc6f8

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Citations in the corpus

Early Life Programming and Neurodevelopmental Disorders (2010, background): “As supported by epidemiological findings, early prenatal stress in mice and guinea pigs has been shown to produce outcomes of increased stress sensitivity in physiological and behavioral measures in male animals (41,42).”
Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation (2013, background): “The hybrid vigor of this background strain provides a reproducible balance of stress responsivity, behavioral performance, and maternal care (Mueller and Bale, 2006, 2007, 2008; Morgan and Bale, 2011).”
11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. (2013, background): “Indeed, the key HPA axis drivers, corticotropin releasing hormone (CRH) and arginine vasopressin (AVP), and feedback receptor, glucocorticoid receptor (GR), show altered expression in models of programming and the promoters of all three encoding genes show persisting changes in methylation in respon”
Sex differences in anxiety and depression clinical perspectives (2014, background): “In this same study, only male placentas showed changes in expression of placental growth genes in response to the stress (Mueller and Bale, 2011).”
Maternal adversity and ecological stressors in natural populations: the role of stress axis programming in individuals, with implications for populations and communities (2013, background): “…and behavioural alterations associated with prenatal stress are accompanied by transcriptional and epigenetic alterations in the brain in genes involved in HPA axis regulation, including altered DNA methylation in promoter regions of the GR and corticotrophin receptor genes (Mueller & Bale 2008).”
Glucocorticoids, prenatal stress and the programming of disease. (2011, neutral): “…MR/GR balance Programmed HPA axis activation has plausibly been ascribed to relative deficiency of glucocorticoid feedback sensitivity with reduced GR and MR in the hippocampus and other feedback sites (Mueller and Bale, 2008; Noorlander et al., 2006; Shoener et al., 2006; Welberg et al., 2000).”
Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review (2014, neutral): “Parental stress Experimental groups—One animal study (44) used a variety of non pain-inducing, nonhabituating stressors over the course of 7 days to stress mouse dams.”
Prenatal Stress, Glucocorticoids and the Programming of Adult Disease (2009, background): “Recent data in the rat has also shown that male, but not female, offspring exposed to stress in early gestation exhibited increased anxiety-related behaviours as adults, again changes associated with sex-differences in placental function (Mueller and Bale, 2008).”