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

Abstract

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 PPAR␣ (peroxisome proliferator-activated receptor ␣), IGFBP-1 (insulin-like growth factor binding protein 1), HIF3␣ (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.

Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction

“…Many of the programmatic changes produced in our EPS mouse model are endophenotypes of neurodevelopmental disorders, including stress dysregulation, cognitive dysfunction, and hypothalamic dysregulation of growth and development (4,(6)(7)(8)(9)(10). These outcomes support the critical communication from the placenta to the fetus related to the bioenergetic or metabolic environment that then programs the hypothalamus, the brain's endocrine and metabolic regulatory center.…”

Sex as a Biological Variable: Who, What, When, Why, and How

“…For instance, in neuropsychiatric diseases such as autism, schizophrenia, or depression, although men and women may be given a similar diagnosis, there exist significant sex differences in overall rates, timing of onset, symptom presentation, and treatment efficacy (Heim and Nemeroff, 1999;Heim and Nemeroff, 2001;Sanchez et al, 2001;Goldstein et al, 2002;Heim et al, 2004;Bale, 2006;Brown and Susser, 2008;Bale, 2009;Brown et al, 2009;Heim et al, 2009;Bale et al, 2010;Heim et al, 2010;Brown, 2012;Davis and Pfaff, 2014;Goldstein et al, 2014). Further, mechanistic animal studies modeling endophenotypes of these disorders have demonstrated robust sex differences in the timing of susceptibility to insults to the developing brain where males appear more vulnerable prenatally and females postnatally (Mueller and Bale, 2006;Mueller and Bale, 2007;Ivy et al, 2008;Kapoor et al, 2008;Mueller and Bale, 2008;Kapoor et al, 2009;Ivy et al, 2010;Hsiao and Patterson, 2012). Therefore, although a male and a female may both be diagnosed with the same disease, for instance autism, the means by which that disease was programmed and presented may be sex-specific.…”

Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure

“…Animal studies have shown that maternal exposure to drugs (10), stress (11), and endocrine disruptors (12) during pregnancy can alter epigenetic gene programming in the brain and contribute to neurodevelopmental deficits in offspring. Several studies have linked gestational (13,14) or neonatal (15,16) BPA exposure to long-lasting changes in DNA methylation and altered gene expression in nonneuronal tissues.…”