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Cystic fibrosis, Huntington disease, Parkinson\u2019s disease, and sickle cell disease are examples of well-known Mendelian disorders that are influenced by exogenous exposures. Environmental factors may act by direct or indirect mechanisms to modify disease severity, timing, and presentation, including through epigenomic influences, protein misfolding, miRNA alterations, transporter activity, and mitochondrial effects. Because pathological features of early-onset Mendelian diseases can mimic later onset complex diseases, we propose that studies of environmental exposure vulnerabilities using monogenic model systems of rare Mendelian diseases have high potential to provide insight into complex disease phenotypes arising from multi-genetic\/multi-toxicant interactions. Mendelian disorders can be modeled by homologous mutations in animal model systems with strong recapitulation of human disease etiology and natural history, providing an important advantage for study of these diseases. Monogenic high penetrant mutations are ideal for toxicant challenge studies with a wide variety of environmental stressors, because background genetic variability may be less able to alter the relatively strong phenotype driving disease-causing mutations. These models promote mechanistic understandings of gene-environment interactions and biological pathways relevant to both Mendelian and related sporadic complex disease outcomes by creating a sensitized background for relevant environmental risk factors. Additionally, rare disease communities are motivated research participants, creating the potential of strong research allies among rare Mendelian disease advocacy groups and disease registries and providing a variety of translational opportunities that are under-utilized in genetic or environmental health science.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab022","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T12:23:40Z","timestamp":1614342220000},"page":"3-12","source":"Crossref","is-referenced-by-count":26,"title":["The Impact of Environmental Factors on Monogenic Mendelian Diseases"],"prefix":"10.1093","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8973-4809","authenticated-orcid":false,"given":"Anke M","family":"Tukker","sequence":"first","affiliation":[{"name":"School of Health Sciences, Purdue University, West Lafayette, Indiana 47907-2051"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charmaine D","family":"Royal","sequence":"additional","affiliation":[{"name":"Departments of African and African American Studies, Biology, Global Health, and Family Medicine and Community Health and Center on Genomics, Race, Identity, Difference, Duke University, Durham, North Carolina 27708"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8728-3346","authenticated-orcid":false,"given":"Aaron B","family":"Bowman","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Purdue University, West Lafayette, Indiana 47907-2051"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2187-2898","authenticated-orcid":false,"given":"Kimberly A","family":"McAllister","sequence":"additional","affiliation":[{"name":"Genes Environment and Health Branch, Division of Extramural Research and Training, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,2]]},"reference":[{"key":"2021111805385452000_kfab022-B1","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1016\/j.neuro.2012.10.009","article-title":"Genetic risk for Parkinson\u2019s disease correlates with alterations in neuronal manganese sensitivity between two human subjects","volume":"33","author":"Aboud","year":"2012","journal-title":"Neurotoxicology"},{"key":"2021111805385452000_kfab022-B2","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.nbd.2014.10.002","article-title":"PARK2 patient neuroprogenitors show increased mitochondrial sensitivity to copper","volume":"73","author":"Aboud","year":"2015","journal-title":"Neurobiol. 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