The interaction of genetic sex and prenatal alcohol exposure on health across the lifespan.

Prenatal alcohol exposure (PAE) can reprogram the development of cells and tissues, resulting in a spectrum of physical and neurobehavioral teratology. PAE immediately impacts fetal growth, but its effects carry forward post-parturition, into adolescence and adulthood, and can result in a cluster of disabilities, collectively termed Fetal Alcohol Spectrum Disorders. Emerging preclinical and clinical research investigating neurological and behavioral outcomes in exposed offspring point to genetic sex as an important modifier of the effects of PAE. In this review, we discuss the literature on sex differences following PAE, with studies spanning the fetal period through adulthood, and highlight gaps in research where sex differences are likely, but currently under-investigated. Understanding how sex and PAE interact to affect offspring health outcomes across the lifespan is critical for identifying the full complement of PAE-associated secondary conditions, and for refining targeted interventions to improve the quality of life for individuals with PAE.

Microbiota and nutrition as risk and resiliency factors following prenatal alcohol exposure.

Alcohol exposure in adulthood can result in inflammation, malnutrition, and altered gastroenteric microbiota, which may disrupt efficient nutrient extraction. Clinical and preclinical studies have documented convincingly that prenatal alcohol exposure (PAE) also results in persistent inflammation and nutrition deficiencies, though research on the impact of PAE on the enteric microbiota is in its infancy. Importantly, other neurodevelopmental disorders, including autism spectrum and attention deficit/hyperactivity disorders, have been linked to gut microbiota dysbiosis. The combined evidence from alcohol exposure in adulthood and from other neurodevelopmental disorders supports the hypothesis that gut microbiota dysbiosis is likely an etiological feature that contributes to negative developmental, including neurodevelopmental, consequences of PAE and results in fetal alcohol spectrum disorders. Here, we highlight published data that support a role for gut microbiota in healthy development and explore the implication of these studies for the role of altered microbiota in the lifelong health consequences of PAE.

Age as a factor in stress and alcohol interactions: A critical role for the kappa opioid system.

The endogenous kappa opioid system has primarily been shown to be involved with a state of dysphoria and aversion. Stress and exposure to drugs of abuse, particularly alcohol, can produce similar states of unease and anxiety, implicating the kappa opioid system as a target of stress and alcohol. Numerous behavioral studies have demonstrated reduced sensitivity to manipulations of the kappa opioid system in early life relative to adulthood, and recent reports have shown that the kappa opioid system is functionally different across ontogeny. Given the global rise in early-life stress and alcohol consumption, understanding how the kappa opioid system responds and adapts to stress and/or alcohol exposure differently in early life and adulthood is imperative. Therefore, the objective of this review is to highlight and discuss studies examining the impact of early-life stress and/or alcohol on the kappa opioid system, with focus on the documented neuroadaptations that may contribute to future vulnerability to stress and/or increase the risk of relapse. We first provide a brief summary of the importance of studying the effects of stress and alcohol during early life (prenatal, neonatal/juvenile, and adolescence). We then discuss the literature on the effects of stress or alcohol during early life and adulthood on the kappa opioid system. Finally, we discuss the few studies that have shown interactions between stress and alcohol on the kappa opioid system and provide some discussion about the need for studies investigating the development of the kappa opioid system.

Moderate Maternal Alcohol Exposure on Gestational Day 12 Impacts Anxiety-Like Behavior in Offspring.

Among the numerous consequences of prenatal alcohol exposure (PAE) is an increase in anxiety-like behavior that can prove debilitating to daily functioning. A significant body of literature has linked gestational day 12 (G12) heavy ethanol exposure with social anxiety, evident in adolescent males and females. However, the association between non-social anxiety-like behavior and moderate alcohol exposure, a more common pattern of drinking in pregnant women, is yet unidentified. To model moderate PAE (mPAE), we exposed pregnant Sprague-Dawley rats to either room air or vaporized ethanol for 6 h on G12. Adolescent offspring were then tested on postnatal days (P) 41-47 in one of the following four anxiety assays: novelty-induced hypophagia (NIH), elevated plus maze (EPM), light-dark box (LDB) and open-field (OF). Our findings revealed significant increases in measures of anxiety-like behavior in male PAE offspring in the NIH, LDB and OF, with no differences observed in females on any test. Additionally, male offspring who demonstrated heightened anxiety-like behavior as adolescents demonstrated decreased anxiety-like behavior in adulthood, as measured by a marble-burying test (MBT), while females continued to be unaffected in adulthood. These results suggest that mPAE leads to dynamic changes in anxiety-like behavior exclusively in male offspring.