Paternal alcohol consumption as a modulator of FASD in a mouse model

Abstract

Fetal Alcohol Spectrum Disorders (FASDs) include a wide range of mental and physical developmental disabilities that leave a lasting impact across the lifetime. Prenatal alcohol exposure most significantly effects the developing brain and facial characteristics, yet not all alcohol exposed pregnancies result in altered brain and facial morphology. Recent compelling evidence for periconceptional environmental factors experienced by both parents and their influence on offspring health has highlighted the need for further research into paternal contributions to FASD.In order to redress the stigma that FASDs are exclusively the mother’s fault, we sought to investigate the environmentally induced patterns of inheritance contributed by both the mother and father as well as their interaction in the establishment of FASD outcomes. We hypothesized that FASD-associated developmental defects would become exacerbated in a dual parental model of alcohol consumption. To test this hypothesis, we exposed both male and female adult C57BL/6J mice to either control or alcohol (10% EtOH) preconception treatment groups using the Drinking in the Dark method of voluntary alcohol consumption. A mating paradigm was used in order to generate control, maternal, paternal, and dual parental alcohol-exposed litters. Upon pregnancy diagnosis on gestational day 10, pregnant females were removed from treatment exposures and the litters were either dissected during late gestation or allowed to continue to birth for postnatal investigations. During gestation we found that maternal, paternal, and dual parental alcohol exposures resulted in distinct craniofacial patterning in both sexes and that both craniofacial patterning and neurological development are parental dose dependent. Beyond the gross morphological level, we implemented RNA sequencing and found distinct changes in the cortical transcriptome between sexes and treatment group. Finally, we sought to investigate whether these changes persisted into later life and found that maternal, paternal, and dual parental alcohol exposures produce unique behavioral phenotypes that are age dependent. Specifically, when both parents consume alcohol, behavioral changes (assessed using novel object recognition, a measure of cognition and memory) can be seen earlier in adolescence, while maternal alcohol induced changes become evident later in adolescence. Importantly, dual parental alcohol exposure also led to decreased mobility in later adulthood indicating early onset of disease.In conclusion, these results fill a large gap in our understanding of the penetrance of FASD and describe the wide variation seen in presenting symptoms. Importantly, we identify paternal alcohol consumption as a significant inducer and contributor to FASD phenotypes. Moreover, these results redress the stigma that maternal alcohol is solely to blame for FASD and elucidate the father’s role in FASD outcomes. This work was supported by a Medical Research Grant from the W.M. Keck Foundation and NIH grant R01AA028219 from the NIAAA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.