Hypothalamic-pituitary-adrenal axis and behavioral dysfunction following early binge-like prenatal alcohol exposure in mice

Abstract

The range of defects that fall within fetal alcohol spectrum disorder (FASD) includes persistent behavioral problems, with anxiety and depression being two of the more commonly reported issues. Previous studies of rodent FASD models suggest that interference with hypothalamic-pituitary-adrenal (HPA) axis structure and/or function may be the basis for some of the prenatal alcohol (ethanol) exposure (PAE)-induced behavioral abnormalities. Included among the previous investigations are those illustrating that maternal alcohol treatment limited to very early stages of pregnancy (i.e., gestational day [GD]7 in mice; equivalent to the third week post-fertilization in humans) can cause structural abnormalities in areas such as the hypothalamus, pituitary gland, and other forebrain regions integral to controlling stress and behavioral responses. The current investigation was designed to further examine the sequelae of prenatal alcohol insult at this early time period, with particular attention to HPA axis-associated functional changes in adult mice. The results of this study reveal that GD7 PAE in mice causes HPA axis dysfunction, with males and females showing elevated corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, respectively, following a 15-min restraint stress exposure. Males also showed elevated CORT levels following an acute alcohol injection of 2.0 g/kg, while females displayed blunted ACTH levels. Furthermore, analysis showed that anxiety-like behavior was decreased after GD7 PAE in female mice, but was increased in male mice. Collectively, the results of this study show that early gestational alcohol exposure in mice alters long-term HPA axis activity and behavior in a sexually dimorphic manner.

Suppressed osteoclast differentiation at the chondro-osseous junction mediates endochondral ossification retardation in long bones of Wistar fetal rats with prenatal ethanol exposure

“…18 / 31 in fetus and caused hyper-responsiveness of hypothalamus-pituitary-adrenal (HPA) axis in offspring (Weinberg et al, 2008;Wieczorek et al, 2015). Our previous work showed that PEE induced the inhibition of fetal HPA axis activity and IUGR production, and the mechanism is associated with the maternal HPA axis activation and high glucocorticoid condition (Liang et al, 2011;Zhang et al, 2014).…”

Effects of prenatal alcohol exposure (PAE): insights into FASD using mouse models of PAE

“…Other mechanisms mediating alcohol’s adverse effects on neurobiological and neurobehavioral outcomes include: nutritional deprivation or deficiencies (e.g., calories, protein, zinc, folate, vitamin A); abnormalities in calcium signaling; altered prostaglandin synthesis/degradation; placental dysmorphology/dysfunction; alcohol-induced circulatory changes in placenta and (or) fetus; disrupted cell–cell interactions (cell adhesion); interference with growth factors or other cell signaling mechanisms that mediate cell proliferation, growth, differentiation, migration, and maturation; oxidative stress and damage by free radicals; disruption of neuronal development in specific cell populations (e.g., serotonergic neurons); alteration/disruption of endocrine balance and neuroendocrine function (Michaelis 1990; Randall et al 1990; West et al 1994; Guerri 1998; Shibley et al 1999; Goodlett et al 2005; Bake et al 2012; Uban et al 2013; Wieczorek et al 2015), and increased neuroinflammation (Weinberg and Gallo 1982; Randall et al 1987, 1989; Weinberg and Bezio 1987; Taylor et al 1988; Weinberg 1989, 1992, 1993; Lee et al 1990, 2000; LeBel and Bondy 1991; Halasz et al 1993; Henderson et al 1995; Kotch et al 1995; Lee and Rivier 1996; Ramanathan et al 1996; Gabriel et al 1998; Bearer 2001 a , 2001 b ; Spong et al 2001; Wilkemeyer et al 2002, 2003; Zhang et al 2005, 2012; Glavas et al 2007; Gubitosi-Klug et al 2007; Weinberg et al 2008; Sari 2009; Dong et al 2010; Bodnar and Weinberg 2013; Dou and Charness 2014; Drew et al 2015; Bodnar et al 2016). …”

“…These studies demonstrate that acute PAE at early gastrulation is sufficient to induce developmental changes in brain and face structure as well as grey matter and white matter tracts that continue well into adolescence. Interestingly, Wieczorek et al found, in an acute model of GD7 PAE, that PAE affects anxiety-like behavior in a sexually dimorphic manner: PAE males showed increases in anxiety-like behavior whereas females exhibited decreases in anxiety-like behavior (Wieczorek et al 2015). …”

The effect of prenatal substance use and maternal contingent responsiveness on infant affect

“…Neurodevelopmental outcomes commonly associated with PAE might be mediated, at least in part, by hypothalamic-pituitary-adrenal (HPA) dysregulation (8) leading to increased stress reactivity and poor stress regulation in PAE children (9). Alternatively, HPA dysregulation and increased stress reactivity in children affected by PAE might be the basis for some of the PAE-induced behavioral deficits (10) and increased vulnerability to secondary psychopathologies, such as mental health problems, inappropriate sexual behavior, and learning disabilities (11). …”