Studies administering chronic, unpredictable stressors to pregnant dams have contributed to the finding that the long-term implications of exposure to stress in utero are sex-specific. Chronic, unpredictable stressors have applicability to human populations, as in daily life humans encounter a variety of unpredictable challenges. The Bale laboratory exposes pregnant mice to a variety of stressors, including loud noises, predator odor, cage changes, and wet bedding at unpredictable times. Offspring exposed to this exhibit reduced corticotrophin-releasing factor (Crf) methylation in the hypothalamus and amygdala and increased GR methylation in adulthood (Mueller and Bale, 2008). Behaviorally, the prenatally stressed animals demonstrate reduced hedonic behavior (decreased sucrose preference), increased depressive-like behavior (increased immobility in the forced swim test) and increased anxiety-like behavior. Intriguingly, these effects were specific to male offspring (Mueller and Bale, 2008). In another study employing prenatal exposure to unpredictable and variable maternal stress, offspring showed increased Bdnf exon IV methylation in the medial prefrontal cortex of males and reduced length of telomeres in both sexes in adulthood (Blaze et al., 2017). Another report found deficits in spatial memory and reduced
