Aneuploid fetal microchimerism: persistence and potential function

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Project Summary: A mother and fetus exchange cells during human pregnancy, and these cells can durably persist as microchimerism, a small amount of foreign genetic material in another individual. Fetal microchimerism has been demonstrated by multiple investigators to be associated with later-life health for the mother, including both risk for and protection from disease. The complexity of these relationships may be further amplified when the fetal microchimerism is genetically abnormal. Trisomy 21, or Down Syndrome, is one of the most commonly seen fetal genetic abnormalities. Some disease risks known to be directly associated with Down Syndrome are reflected in the health of women with Down Syndrome offspring. For example, individuals with Down Syndrome are at high risk for the development of Alzheimer’s Disease. Interestingly, mothers of Down Syndrome offspring have been shown to have an increased incidence of Alzheimer’s Disease themselves. The cause of this association is unknown; however, one hypothesis is that genetically abnormal microchimeric cells could serve as a nidus for disease. On the other hand, microchimerism from a Trisomy 21 fetus may also have potential benefit, particularly related to risk of malignancy. Individuals with Down Syndrome have significantly lower than expected risks of solid tumors, especially breast cancer. In general, fetal microchimerism has been shown to be protective for the development of breast cancer; some hypothesize this relationship to reflect additional immune surveillance from the microchimeric “graft” for elimination of precancerous cells. These observations raise the question whether microchimerism from a Trisomy 21 pregnancy may translate into additional protection when the mother acquires cells particularly protective for solid tumor development. To directly implicate genetically abnormal microchimerism as a contributing factor, its persistence after pregnancy and its functional capacity must be demonstrated. This proposal aims to identify fetal microchimerism in women who have had a pregnancy complicated by Trisomy 21 and to directly evaluate the genetic makeup and gene expression of microchimeric cells. If demonstrated, information from these studies could yield targets for therapy to maximize health in women with exposure to genetically abnormal microchimerism, as well as for more broadly defined populations. Insights gained from this work have potential benefit for women who have experienced a Trisomy 21 pregnancy, for their offspring directly, and, insofar as mechanisms of disease can be elucidated, the larger populations affected by diseases including Alzheimer’s Disease and breast cancer.