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Hybrid Mice Affect The Penetrance Of FASD In Offspring – A Precedent To Diversify Our Mouse Models

By Sanat Bhadsavle | Ph.D. student in Biomedical Sciences

Diagram showing mice strains and placental development in FASD.

Fetal alcohol spectrum disorders (FASD) result from maternal alcohol consumption during pregnancy, causing developmental defects like fetal growth restriction, facial abnormalities, and neurological problems. The healthcare costs for FASD in the United States range from $926 million to $3 billion over a lifetime. While maternal alcohol consumption is a known cause of FASD, recent animal studies suggest paternal drinking before conception also contributes to FASD.

Most animal research uses inbred mouse strains (mice that are the offspring of the same parent DNA) because it is easier to control for genetic variables. However, inbred strains lack the level of genetic diversity present in the natural world, thus limiting their translation to human medicine. This study investigates FASD in hybrid mice — mice that are the offspring of two inbred strains and have greater genetic diversity — to replicate previously reported FASD phenotypes, including fetal growth restriction (small fetus) and placental overgrowth.

Placental overgrowth is when the placenta — a temporary organ formed during pregnancy that provides nutrition and oxygen to the fetus — increases in size and weight to provide adequate nutritional support to the growing fetus due to stressful situations. Prior studies in our lab showed placental overgrowth in offspring of alcohol-exposed fathers using the inbred C57BL/6J strain. This study used the 129S1/SvlmJ strain, which is prone to placental defects, hypothesizing that paternal alcohol exposure would heighten offspring sensitivity to placental anomalies.

Unexpectedly, hybrid offspring placentae showed a less severe phenotype than inbred models. Male offspring exhibited slight placental overgrowth, which was not seen in females. We found that genes that protect our cells from oxidative damage, — a form of cell injury that leads to DNA damage — were upregulated in the female placenta but not in males, suggesting these pathways may protect female babies against the effects of alcohol. Histological analysis revealed structural differences in hybrid offspring placentae compared to C57BL/6J mice, possibly explaining the observed protection.

Ultimately, this study found that hybrid mice strains do not behave similarly to inbred strains, which highlights the importance of genetic diversity and emphasizes the need to diversify mouse models to significantly enhance the relevance of animal studies to human health.

Filling The Gap: Down Syndrome, Bone Health, And Fracture Healing

Filling The Gap: Down Syndrome, Bone Health, And Fracture Healing

By Kirby Sherman | Ph.D. candidate in Biomedical Sciences
Department of Veterinary Physiology & Pharmacology

Down syndrome (DS), the most common birth defect in the United States, alters human development and leads to a variety of clinical issues, including low bone mass and strength. Because people with DS are living longer, more active lives, their risk of bone fracture has increased.

However, there is a significant gap in knowledge regarding DS and fracture healing, and it remains unknown if people with DS are able to heal fractures. This observation of the lack of research surrounding DS and bone health was first made in the laboratory of Dr. Larry Suva, in the School of Veterinary Medicine & Biomedical Sciences Department of Veterinary Physiology & Pharmacology. Indeed, the risk of fractures is a major health concern for the DS community and can severely impact their quality of life.

Due to the increased risk resulting from decreased bone mineral density observed in DS people, our work sought to understand how DS impacts the ability to heal a fracture. Ultimately, we determined that when individuals with DS fracture a bone, that bone is unlikely to heal. We also discovered the reason why these bones fail to heal (called non-union), namely inflammation and a defect in bone repair.

Importantly, fractures that fail to heal can be fatal, even in young people with no previous health concerns. With this new awareness of the problem, we hope there will be more widespread adoption of measures to increase bone strength, more careful monitoring when fractures do occur, and that physicians and others will consider the bone health of people with DS a priority for their care.