Effects of early-life adversity on immune function are mediated by prenatal environment: Role of prenatal alcohol exposure

Abstract

The contribution of the early postnatal environment to the pervasive effects of prenatal alcohol exposure (PAE) is poorly understood. Moreover, PAE often carries increased risk of exposure to adversity/stress during early life. Dysregulation of immune function may play a role in how pre- and/or postnatal adversity/stress alters brain development. Here, we combine two animal models to examine whether PAE differentially increases vulnerability to immune dysregulation in response to early-life adversity. PAE and control litters were exposed to either limited bedding (postnatal day [PN] 8-12) to model early-life adversity or normal bedding, and maternal behavior and pup vocalizations were recorded. Peripheral (serum) and central (amygdala) immune (cytokines and C-reactive protein - CRP) responses of PAE animals to early-life adversity were evaluated at PN12. Insufficient bedding increased negative maternal behavior in both groups. Early-life adversity increased vocalization in all animals; however, PAE pups vocalized less than controls. Early-life adversity reduced serum TNF-α, KC/GRO, and IL-10 levels in control but not PAE animals. PAE increased serum CRP, and levels were even higher in pups exposed to adversity. Finally, PAE reduced KC/GRO and increased IL-10 levels in the amygdala. Our results indicate that PAE alters immune system development and both behavioral and immune responses to early-life adversity, which could have subsequent consequences for brain development and later life health.

Keywords: Amygdala; C-reactive protein; Cytokines; Early-life adversity; Maternal behavior; Prenatal alcohol exposure; Rat.

Figure 1

Maternal behavior of mothers that consumed alcohol during pregnancy and were exposed to insufficient bedding for nest building. Bars represent mean ± SEM of total nursing (A), arched-back nursing (B), blanket nursing (C), passive nursing (D), licking and grooming (E), self-directed behaviors (F), negative maternal behaviors (G), and behavioral consistency (H) from PN8-12. § indicates significant main effect of bedding, where all mothers exposed to insufficient bedding were different from mothers exposed to abundant bedding, independent of gestational group (n = 15–17 for all groups).

Figure 2

Vocalization of pups that were exposed to alcohol during gestation and/or were exposed to early-life adversity. Bars represent mean ± SEM of total number of vocalizations from PN8-12. * indicates that normally reared PAE pups vocalized less than normally reared control pups; ❖ indicates that PAE and control pups normally reared vocalized less than PAE and control pups exposed to adverse rearing; ‡ indicates that PAE pups exposed to adverse rearing vocalized less than control pups exposed to adverse rearing (n = 15–17 for all groups).

Figure 3

Serum CRP levels in pups that were exposed to alcohol during gestation and/or were exposed to early-life adversity. Bars represent mean ± SEM of serum CRP levels at PN12. § indicates significant main effect of rearing condition, where all pups exposed to adverse rearing showed higher CRP levels than pups exposed to normal rearing, independent of prenatal treatment; † indicates significant main effect of prenatal treatment, where all PAE pups showed higher CRP levels than control pups, independent of rearing condition (n = 12–14 for all groups).

Figure 4

Serum cytokine levels in pups that were exposed to alcohol during gestation and/or were exposed to early-life adversity. Bars represent mean ± SEM of serum KC/GRO (A), IL-10 (B), TNF-α (C), IFN-γ (D), IL-4 (E), IL-5 (F), and IL-2 (G) levels at PN12. § indicates significant main effect of rearing condition, where all pups exposed to adverse rearing showed lower IFN-γ levels than pups exposed to normal rearing, independent of prenatal treatment; # indicates that control pups exposed to adverse rearing showed lower KC/GRO, IL-10, and TNF-α levels than control pups exposed to normal rearing based on a priori comparison (n = 11–13 for all groups, excluding IL-4, IL-5 and IL-2 that were not analyzed statistically).

Figure 5

Amygdala cytokine levels in pups that were exposed to alcohol during gestation and/or were exposed to early-life adversity. Bars represent mean ± SEM of amygdala KC/GRO (A), IL-10 (B), TNF-α (C), IFN-γ (D), IL-4 (E), IL-5 (F), and IL-1β (G) levels at PN12. § indicates significant main effect of rearing condition, where all pups exposed to adverse rearing showed higher KC/GRO levels than pups exposed to normal rearing, independent of prenatal treatment; † indicates significant main effect of prenatal treatment, where all PAE pups showed higher KC/GRO levels than control pups, independent of rearing condition; # indicates that PAE pups exposed to normal rearing showed higher IL-10 levels than control pups exposed to normal rearing based on a priori comparisons (n = 11–15 for all groups).