The Impact of Environmental Factors on Monogenic Mendelian Diseases

Abstract

Environmental factors and gene-environment interactions modify the variable expressivity, progression, severity, and onset of some classic (monogenic) Mendelian-inherited genetic diseases. Cystic fibrosis, Huntington disease, Parkinson’s 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.

Although “monogenic” Mendelian disorders are defined as typically rare diseases arising from single gene defects with high penetrance, it has become increasingly apparent that these diseases frequently exhibit much more complex and diverse phenotypic presentations than originally appreciated (O’Neal and Knowles, 2018). Some Mendelian monogenic diseases show variable onset and expression of clinical manifestations of disease traits (Peltonen et al. 2006), whereas other individuals who carry known Mendelian deleterious mutations appear to be completely healthy or resilient (Chen et al., 2016). The variable expressivity and alterations in progression, severity, onset, and penetrance of some rare Mendelian diseases could be due to environmental factors and gene-environment interactions (Chao et al., 2018; Noyce et al., 2012). Individuals with monogenic diseases may be the most genetically susceptible or vulnerable to a variety of environmental exposures (Chung and Karlsen, 2017; Kannarkat et al., 2015). Moreover, many common human diseases have both a Mendelian and more complex polygenic class of disease and are often described as a continuum from “extreme” Mendelian forms to complex disease phenotypes (Freund et al., 2018). Although the focus on genome-wide association studies and the rapid reduction in sequencing costs have moved many researchers away from Mendelian diseases, we argue here for the continued value of studying monogenic diseases in revealing critical pathways for both rare Mendelian and more common complex disease types. As one example, the Centers for Mendelian Genomics is one large-scale effort that is currently identifying genes underlying Mendelian diseases (Chong et al., 2015). Many molecular and pathological insights about common human diseases have originated from the rare familial (usually early onset) forms of these diseases (Peltonen et al., 2006). The identification of genes for Mendelian and rare familial forms of common diseases have in many cases identified new biological pathways or protein interactions that had not previously been associated with a particular disease phenotype (Peltonen et al., 2006). These discoveries have helped pave the way for new diagnostic or therapeutic options relevant to both rare and common diseases (Chong et al., 2015). For example, insights into more common forms of Parkinson’s disease have come from studying Gaucher disease, and molecular insights relevant to Alzheimer’s disease have come from studying the rare Niemann-Pick disease type C (Hassan et al., 2017). Recent studies suggest biological pathways are shared between Mendelian and complex diseases and that in many cases, genetic coding variant mutations may lead to Mendelian disease and noncoding variants in the same gene(s) may produce complex traits (Freund et al., 2018). In a similar fashion, exploration of environmental influences on these Mendelian diseases with common disease counterparts may also uncover unique mechanistic understandings of gene-environment interactions and biological pathways relevant to related common disease outcomes.

In this review, we use examples of classic well-defined Mendelian disorders where environmental factors strongly impact disease onset and pathogenesis to argue the value of this approach to understanding more complex human chronic diseases. Table 1 lists some of the key environmental risk factors for these particular Mendelian diseases. We will highlight some potential broad processes and molecular mechanisms whereby exposures have an impact on Mendelian disease outcomes and address what can be learned from further research endeavors in this field.

Table 1.

Environmental Factors Affecting Classic Mendelian Disease Presentations

Disease	Environmental risk factor	Reference
Cystic fibrosis	Pathogenic microorganisms Tobacco smoking E-cigarette vaping Air pollution Dietary factors Temperature	Wolfenden and Schechter (2009), Collaco et al. (2010), Collaco et al. (2011), Schindler et al. (2015), Garcia-Arcos et al. (2016), Ong et al. (2017), Brugha et al. (2018), Hooper and Kaufman (2018), Gotts et al. (2019)
Huntington disease	Housing conditions Environmental stimulations Physical activity Stress Caloric restrictions Dietary factors Manganese bioavailability	Williams et al. (2010), Mazarakis et al. (2014), Mo et al. (2015), Bichell et al. (2017), Bryan et al. (2019), Bryan et al. (2020), Pfalzer et al. (2020)
Parkinson’s disease	Tobacco smoking Coffee/tea Dietary factors β2-adrenoreceptor agonists/antagonists Physical activity Vitamin E Gout NSAIDs Manganese Copper Pesticides	Chen et al. (2015), Ascherio and Schwarzschild (2016), Brouwer et al. (2017), Hughes et al. (2017), Simon et al. (2017), Cao et al. (2019), Kochmanski et al. (2019), Belvisi et al. (2020)
Sickle cell disease	Climate-related factors (temperature, humidity, high altitudes, etc.) Air pollution Tobacco smoking Physical exercise SES-related factors Dietary factors	Hyacinth et al. (2010), Tewari et al. (2015), Piel et al. (2017a,b), Yarboi et al. (2017), Crouch et al. (2018), Martin et al. (2018), Parriault et al. (2019), Xu and Frenette (2019), Bills et al. (2020), Blumberg et al. (2020), Karlson et al. (2020), Wachnian et al. (2020)

MONOGENIC MENDELIAN DISEASES WITH SUBSTANTIAL ENVIRONMENTAL INFLUENCES

 

Cystic Fibrosis

Cystic fibrosis is one of the most common Mendelian diseases. It is characterized by progressive damage to the respiratory system. Although mutations in only one gene, the cystic fibrosis transmembrane conductance regulator (CFTR), generally determine the presence or absence of cystic fibrosis, clinical outcomes vary greatly in individuals even with the same CFTR genotype (Drumm et al., 2012). In general, there is a genotype-phenotype correlation with disease features (Wolfenden and Schechter, 2009). Nongenetic factors may account for approximately half of the clinical variation in cystic fibrosis (Collaco et al., 2010). The clinical course of cystic fibrosis has been shown to be affected by pathogenic microorganisms, environmental tobacco smoke, e-cigarette vaping, air pollutants including ozone (O₃) and particulate matter (PM_{2.5 or 10}), as well as dietary factors such as high fat and high calorie intake (Collaco et al., 2010; Garcia-Arcos et al., 2016; Gotts et al., 2019; Hooper and Kaufman, 2018; Ong et al., 2017; Schindler et al., 2015; Wolfenden and Schechter, 2009). The exact CFTR mutation appears to affect the impact of some of these environmental risk factors, particularly secondhand smoke, on lung disease severity (Collaco and Cutting, 2008). Specifically, several studies have shown an association between ambient air pollution and pulmonary exacerbations in patients with cystic fibrosis (Brugha et al., 2018). Researchers have determined that cystic fibrosis patients’ lungs are particularly vulnerable to the impacts of air pollution in the form of particulate deposition (Goss et al., 2004). Infection by Pseudomonas aeruginosa in the airway is associated with a more rapid decline in lung function in patients with cystic fibrosis as well (Psoter et al., 2015). In addition, temperature appears to affect lung disease and infection in cystic fibrosis patients with patients living in areas with warmer ambient temperatures having a higher prevalence and an earlier initial age for P. aeruginosa acquisition (Collaco et al., 2011).

Huntington Disease

Huntington disease is a progressive brain disorder viewed as a classic Mendelian autosomal dominant disease caused by a CAG triplet repeat expansion in the huntingtin gene with high penetrance of 40 or higher (to 120) tandem repeats (McColgan and Tabrizi, 2018). However, Huntington disease progression was found to be delayed in transgenic Huntington disease mice harboring a long CAG repeat by enriched housing conditions and a variety of environmental stimulations (Mazarakis et al., 2014). Animal and human preclinical studies have found environmental interventions that can delay the common motor, cognitive, and other neurodegenerative symptoms of Huntington disease. These environmental alterations in Huntington disease mouse models included the addition of novel objects of varied textures and shapes, stimulating structures for climbing, and increased nesting and bedding materials. Various physical, cognitive, and occupational therapies have now been applied to Huntington disease patients which have improved motor function as well. Physical activity, stress, and dietary interventions or caloric restriction also appear to modulate Huntington disease progression (Mo et al., 2015). In addition, a prominent neuroprotective gene-environment interaction with the huntingtin mutant gene and manganese (Mn) has been identified. Mn exposure reduces Huntington disease phenotypes and the Huntington disease genotype reduces effects of toxic Mn exposures (Bichell et al., 2017; Bryan et al., 2019, 2020; Pfalzer et al., 2020; Williams et al., 2010). The presence of a heavy metal modifier substantially affecting a classic Mendelian disease pathology in animal and rodent models sets the stage for many other explorations of previously unidentified environmental factors in other Mendelian diseases. In the case of Huntington disease, further research into the interaction of Mn and the Huntingtin protein has led to a better mechanistic understanding of the etiology of this neurodegenerative disease and the mechanisms of Mn neurotoxicity (Bichell et al., 2017; Stansfield et al., 2014; Tidball et al., 2014; Warren et al., 2020).

Parkinson’s Disease

Parkinson’s disease is a prevalent chronic, progressive neurodegenerative disease caused by selective dopaminergic neurodegeneration within the substantia nigra and the presence of protein aggregates known as Lewy bodies. Mutated forms of α-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2) are found in Lewy bodies which cause genetic forms of inherited Parkinson’s disease. Parkinson’s disease is intriguing in that it has both rare monogenic forms that are associated with highly penetrant gene variants in SNCA, LRRK2, and other genes but also much more common idiopathic forms that have strong contributions from both low penetrant genetic risk factors and environmental risk factors that elicit a “parkinsonism” phenotype. There are also rare forms on the opposite side of the spectrum induced by high doses of single neurotoxicants, such as manganese (Chen et al., 2015; Petrucci et al. 2014), though even single neurotoxicants, like manganese, may be environmental risk factors for multiple diseases (Balachandran et al., 2020). Thus, the monogenic and single environmental/toxicant forms in Parkinson’s disease are contrasted by the more common complex disease presentations. This complex disease form is generally attributed to the interaction of many genetic and environmental variants (Petrucci et al., 2014). Prospective longitudinal studies suggest that a variety of environmental factors impact Parkinson’s disease. Cigarette smoking, coffee, tea, β2-adrenoreceptor agonists/antagonists, physical activity, intake of milk and dairy products, vitamin E, gout, and some nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, can be considered as probable or possible risk/protective factors for Parkinson’s disease (Ascherio and Schwarzschild, 2016; Belvisi et al., 2020; Hughes et al., 2017; Simon et al., 2017). In addition, there is reasonably strong epidemiological evidence for the association of some specific environmental toxins/toxicants and pesticides with Parkinson’s disease monogenic-associated disease genes, particularly rotenone, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), Cu, Mn, dieldrin, maneb, and zieram (Brouwer et al., 2017; Cao et al., 2019; Kochmanski et al., 2019). Various modifiable environmental protective factors for Parkinson’s disease are beginning to be explored as potential effective interventions or preventions (Belvisi et al., 2020).

Sickle Cell Disease

Sickle cell disease has a heterogeneous presentation, typically characterized by recurrent pain and organ damage caused by the formation of sickled erythrocytes (Piel et al., 2017a; Tewari et al., 2015). Although the genetic basis for this disorder, a point mutation in the β-globin chain of the hemoglobin gene, is well understood, the sickle cell disease genotype only accounts for a small portion of the variation in phenotype and clinical presentation of the disease (Piel et al., 2017b; Tewari et al., 2015). Studies have shown that the range of sickle cell disease severity is associated with exposures to diverse environmental factors, including temperature, wind, humidity, high altitudes, and air pollutants, among other climate-related phenomena (Parriault et al., 2019; Piel et al., 2017b; Tewari et al., 2015; Wachnian et al., 2020; Xu and Frenette, 2019). The clinical hallmark of sickle cell disease, pain episodes (vasoocclusive crises—VOCs), are associated with wind exposure, large temperature fluctuations, cold temperatures, and decreased air humidity (Parriault et al., 2019). Interestingly, higher concentrations of atmospheric carbon monoxide and lower atmospheric pressure may be beneficial for individuals with sickle cell disease. Physical exercise is associated with variations in sickle cell disease outcomes, with intense acute exercise sometimes leading to death (Martin et al., 2018), whereas low to moderate exercise sometimes helps to reduce VOC-related pain (Karlson et al., 2020). Active and passive smoking have been found to be detrimental to individuals with sickle cell disease (Tewari et al., 2015). Social factors such as socioeconomic status and neighborhood can influence exposure to urban air pollution including traffic-related pollutants and have been found to exacerbate sickle cell disease symptoms as well (Bills et al., 2020; Blumberg et al., 2020; Piel, Steinberg, et al., 2017; Yarboi et al., 2017). Lastly, some dietary factors have also been implicated in sickle cell disease outcomes, although more research is needed to explore this link (Crouch et al., 2018; Hyacinth et al. 2010).

POTENTIAL AVENUES FOR TOXICANT VULNERABILITY IN MENDELIAN DISEASE

The mechanisms by which environmental agents might affect Mendelian disease onset, severity, or phenotypic presentation may be directly or indirectly related to the pathogenic mutation. These mechanisms include gene-environment interactions (altered genetic susceptibility to toxicants that themselves directly lead to disease), or convergence of additive impacts by environmental risk factors on the biological pathways that are directly altered by monogenic Mendelian disease genes. Examples of direct gene-environment interactions have been identified in the case of rotenone, paraquat, and MPTP impacting Parkinson’s disease risk via particular Parkinson’s disease gene mutations (Belvisi et al., 2020; Helley et al., 2017). Genetic mutations allow for substantially increased susceptibility or sensitivity to environmental risk factors in some cases. For example, genetic susceptibility to environmental factors linked to human leukocyte antigen (HLA) variants that alter HLA expression and immune responses seem to increase Parkinson’s disease risk (Kannarkat et al., 2015). Paraquat and other environmental toxicants have also been directly implicated in causing the primary dopamine cell death associated with Parkinson’s disease as dopamine active transporters take up this herbicide (Atsushi and Tamano, 2020; Richter et al., 2017). Many other environmental risk or protective factors for Parkinson’s disease have shown biological plausibility for impacting the nigrostriatal dopaminergic system as well (Aboud et al., 2012, 2015; Belvisi et al., 2020). In other cases, the environmental factors may indirectly affect biological pathways or networks previously implicated with genetic variant effects that ultimately converge to lead to the same pathophysiology related to the disease. For example, a number of conserved transcriptional pathways have been implicated for pesticide-induced neurotoxicity in Parkinson’s disease (Cao et al., 2019). The pesticides maneb, rotenone, and paraquat all affect ALDH2, TH, and SLC18A2 genes that contribute to dopamine metabolism. Further, these pesticides alter the number of transcripts of the SNCA and TNF (tumor necrosis factor; Cao et al., 2019). These data support the hypothesis that reducing pesticide exposure may reduce Parkinson’s disease risk. With regard to cystic fibrosis, environmental exacerbation through secondhand smoke may occur through regulation of fatty acid metabolism and activation of mitogen-activated protein kinase pathways in human airway epithelial cells (Kopp et al., 2016; Zielen and Fussbroich, 2019). For sickle cell disease, environmental factors such as wind speed and temperature are known to alter central and neural pain mechanisms, resulting in increased heat and cold sensitivity through central nervous pain sensitization (Brandow et al., 2013). In the sections below, we highlight five specific molecular mechanisms that have been explored in recent research. These general mechanisms may explain some of the ways in which environmental factors may impact monogenic disease.

 

Alterations in Epigenetic Machinery

The dynamic epigenetic regulation is widely seen as the interface between the stable coding portion of the genome and the ever-changing environment, with epigenetic mechanisms contributing in a variety of ways to how environmental influences might contribute to disease development (Bakulski and Fallin, 2014). Some Mendelian genetic disorders have now been identified that are associated with various alterations in specific epigenetic machinery that are caused by either genetic mutations, environmental factors, or both (Bakulski and Fallin, 2014). Specifically, disruptions of histone lysine acetylation and methylation, as well as DNA cytosine methylation, have been shown for Mendelian diseases (Leppert and Matarazzo, 2014). Some environmental influences have been found to affect these epigenetic marks in some Mendelian disorders as well (Fahrner and Bjornsson, 2014; Harris et al., 2019). The exploration of these Mendelian disorders of epigenetic machinery have led to insights into the imbalance of chromatin states and the levels of methylation and their possible role in human disease pathogenesis in general. Epigenomic changes have also been indirectly linked to numerous neurodegenerative disorders. Parkinson’s and Huntington disease, for example, both illustrate disturbances in various epigenetic marks (including methylation, chromatin remodeling, and histone marks; Wassouf and Schulze-Hentrich, 2019). Recent evidence suggests that Mn may play a role in neurotoxicity and susceptibility to Parkinson’s disease through epigenetic mechanisms as well (Tarale et al., 2016). Potential pharmaceutical therapeutic applications for restoring balance of chromatin states and alteration of methylation patterns with DNA methyltransferases are starting to be explored in these Mendelian disorders of epigenetic machinery, which may contribute to a better understanding of epigenomic manipulations that might have broad applicability for epigenetic-based therapies for many human diseases (Fahrner and Bjornsson, 2014; Leppert and Matarazzo, 2014). The reversibility of epigenetic regulations offers a potential for targeted therapies and intervention in the future (Wassouf and Schulze-Hentrich, 2019). One example is the use of several pharmacological therapies to affect epigenetic regulation to control polymerization of mutated sickle hemoglobin in red blood cells in sickle cell disease (Molokie et al., 2017).

MicroRNA

MicroRNAs (miRNAs) may be one specific RNA-based epigenetic feature that provides a mechanistic link for how environmental exposures may impact certain Mendelian diseases, unappreciated until recently. These small noncoding single-stranded RNAs are transcribed as a stem-loop structure and bind in a sequence-specific manner at the 3′-UTR of mRNAs (Singh and Yadav, 2020). miRNA dysregulation is becoming increasingly recognized as a mechanism relevant to some Mendelian disease development. miRNAs can regulate gene expression post-transcriptionally in a versatile manner because 1 miRNA can target numerous mRNAs, and 1 mRNA can be targeted by different miRNAs (Wallace et al., 2020). Several recent reports have implicated alterations in miRNAs to explain the extreme variability in onset, progression, and severity of some Mendelian disease presentations, particularly for lysosomal storage disorders and Mendelian inflammasome-associated autoinflammatory diseases (Hassan et al., 2017; Surace and Hedrich, 2019). It also appears that many environmental factors can affect miRNAs, and these miRNA changes can in turn lead to the pathology of both complex and monogenic human diseases. For example, some miRNAs appear to regulate neurotoxicant-induced neurodegeneration in the brain in Parkinson’s disease, spinocerebellar ataxias, and other neurodegenerative diseases (Singh and Yadav, 2020; Wallace et al., 2020). There is a growing body of evidence suggesting that environmental exposures often impact gene expression through alteration of miRNAs, and miRNAs are currently being explored as promising biomarkers for environmental exposures due to their stability, tissue specificity, and ease of measurement (Kotsyfakis and Patelarou, 2019; Vrijens et al., 2015; Wallace et al., 2020).

Transporter Activity

Cellular transporter activity has been shown to impact onset of some Mendelian diseases. Individuals with mutations in the Mn efflux transporter SLC30A10 and uptake transporter SLC39A14 are especially sensitive or susceptible to exposure to environmental Mn (Anagianni and Tuschl, 2019). Familial Parkinson’s disease has also been reported as a result of a mutation in SLC30A10. These mutations prevent this transporter from travelling to its location on the cell surface, thereby preventing it from fulfilling its role in Mn efflux mediation (Leyva-Illades et al., 2014). Patients with a mutation in SLC39A14 accumulate excessive Mn, resulting in rapid progressive childhood-onset parkinsonism dystonia (Tuschl et al., 2016). Thus, inherited mutations in manganese transporters are a genetic predisposition for the development of Parkinson’s disease. In addition, altered systemic metal levels can lead to changes in metal transporters that shift vulnerability to toxicity of co-transported metals (Smith et al., 2013; Venkataramani et al., 2018). For example, excess or deficient iron diets and excess Mn exposures can all affect the expression and function of transferrin receptor and divalent metal transporter 1 to influence tissue and cellular levels of the other metal (Amos-Kroohs et al., 2015; Garcia et al., 2006; Thompson et al., 2007; Wang et al., 2008). Research into these transporter mutations and environmental factors that modify transporter activity is likely to reveal new information on the role of Mn in the development of Parkinson’s disease, related disorders, or Mn-related diseases.

Protein Misfolding

Protein misfolding is another mechanism whereby environmental exposure may impact monogenic disease development. Recent research has focused on the induction by environmental exposures of protein unfolding/misfolding and/or proteasomal degradation in some rare Mendelian diseases. Specifically, exposures such as cigarette smoke, air pollution, and some infectious agents and pathogens originating from the air have been shown to be associated with endoplasmic reticulum (ER) stress and protein misfolding in some chronic lung diseases (including CF) and may contribute to both the initiation and progression of lung disease by activation of the unfolded protein response (UPR; Wei et al., 2013). The UPR is a highly conserved biological pathway that attempts to restore cellular homeostasis when unfolded protein accumulation leads to the activation of ER transmembrane transducers (Wei et al., 2013). Additionally, abnormal S-nitrosylation caused by environmentally induced nitrosative and oxidative stress triggers protein misfolding and may contribute to the great majority of sporadic cases of neurodegenerative diseases having rare familial forms, including in Huntington and Parkinson’s disease (Nakamura et al., 2015). In the case of Parkinson’s disease, both genetically and environmentally induced forms of the disease have been found to be strongly linked to altered post-translational modifications of α-synuclein and LRRK2 (Harischandra, Ghaisas, et al., 2019; Harischandra, Rokad, et al., 2019). Research suggests that phosphorylation, ubiquitination, nitration, and/or truncation (all potentially impacted by environmental exposures) appear to affect the structure, stability, localization, and function of SNCA and LRRK2 proteins (Pajarillo et al., 2019). A variety of pesticides also appear to accelerate the onset of Huntington disease by influencing the aggregation of the mutant Huntingtin protein (Deshmukh et al., 2012). Studying the direct effects of exposures on protein misfolding in some of these rare diseases may lead to a greater understanding of gene-environment interactions relevant to many disease phenotypes that are associated with functional protein conformational changes.

Mitochondrial Effects

Mitochondrial dysfunction is also seen as a common target that can be implicated in both genetic mutations and environmental risk factors relevant to many monogenic Mendelian diseases (Zhang et al., 2020). This is specifically true for Parkinson’s disease, where α-synuclein is known to directly induce mitochondrial dysfunction in vivo. Many of the gene variants implicated in familiar Parkinson’s disease play a role in autophagy and mitophagy and thus affect mitochondrial dysfunction indirectly as well. In fact, mitochondrial dysfunction appears to be a common route for the link or convergence of both genetic variants and environmental neurotoxicants to Parkinson’s disease through multiple interconnected direct and indirect molecular mechanisms, including impacts on mitochondrial dynamics and function (fission, fusion, and transport), increased apoptosis, impaired autophagy, ubiquitin-proteasome systems, increased ROS production, and mitochondrial DNA damage (Helley et al., 2017). Mitochondrial dysfunction in general is a hallmark feature of many Mendelian neurodegenerative diseases (including Huntington disease) and understanding the impact of environmental factors on mitochondrial dysfunction mechanisms could lead to a variety of therapeutic treatments (Panchal and Tiwari, 2019).

FUTURE DIRECTIONS

Well-established Mendelian animal models can be used as a tool to study perturbances caused by environmental exposures on the molecular or biochemical pathways affecting many complex diseases. Many animal models of Mendelian diseases are already thoroughly characterized, readily available, and often recapitulate the human disease phenotype better than most complex common disease model organisms. Because both phenotypes and molecular mechanisms of some early-onset Mendelian diseases mimic later-onset complex diseases, insights gained from future studies with Mendelian model organisms will logically be applicable to biological pathways that are disrupted in complex human diseases. Also, these Mendelian animal models are ideal for environmental challenge studies, because all other variables can be more easily controlled in monogenic disease models than in complex models. Moreover, some of the genetic mutations render these models more susceptible to environmental insults. For example, physical activity, as well as stress, have been explored in both neurotoxicant-induced and genetic rodent Parkinson’s disease models. These studies contributed to a greater understanding of the impact of these exposures on dopaminergic neurons (Wassouf and Schulze-Hentrich, 2019). Recently, the mechanism whereby rapid influx of divalent Zn cation with extracellular glutamate accumulation causes nigrostriatal dopaminergic degeneration has been explored in a paraquat-induced Parkinson’s disease rat model (Tamano et al., 2019). A combined MPTP neurotoxin with a genetic model for Parkinson’s disease is now being investigated as a promising animal model to provide insights into the complex multifactorial nature of Parkinson’s disease (Kin et al., 2019).

In addition to established mammalian (eg, rodent) models, many other in vivo, in vitro, and in silico models have utility to further understand the impact of environmental exposures or genetic and environmental modifiers on Mendelian disease onset and progress. A variety of lower model organisms, including Drosophila, C. elegans, and zebrafish are being explored. Population-based model organisms such as the Collaborative Cross and Diversity Outbred, combined with recent advances in a variety of in vitro approaches (especially genome editing tools such as CRISPR/Cas9, high-throughput toxicity screens, embryonic stem cells, and [human] induced pluripotent stem cells [iPSCs]), could allow the introduction of a Mendelian disease variant to be explored across a range of genetic and environmental backgrounds. Recent advances in human iPSCs have allowed them to be a strong tool for in vitro disease modeling by duplicating the human gene variant and the corresponding disease phenotypes in an in vitro setting (Tobe et al., 2011). Recent efforts have utilized human iPSCs to specifically model Mendelian diseases in a cell-specific context (Kouroupi et al., 2017), or in a 3D environment to more closely resemble the in vivo brain (Chlebanowska et al., 2020; Kim et al., 2019; Smits et al., 2019). These efforts could be further exploited to incorporate environmental toxicants. Computational toxicology is also starting to be utilized to probe how environmental toxicants may perturb interacting signaling and molecular pathways leading to Mendelian disease (Cao et al., 2019).

CONCLUSIONS

Rare disease communities and broad-based coalitions (eg, the Genetic Alliance) comprise motivated research participants and drivers of research who could accelerate strong research partnerships with environmental health scientists that have not been explored extensively. Rare disease networks could provide powerful human research cohorts of sufficient power for meaningful analysis of gene-environment interactions for rare monogenic diseases. Certainly, many untapped collaborations exist for interactions with several NIH Institutes, as well as the Office of Rare Diseases Research and the National Organization of Rare Diseases, that focus and/or award both basic and translational rare disease research.

The ability for environmental exposures to impact Mendelian disease outcomes can also have regulatory consequences. A recent policy (the Frank R. Lautenberg Chemical Safety for the 21st Century Act) requires the U.S. Environmental Protection Agency to evaluate chemicals with specific consideration to susceptible populations of all types (including genetic susceptibility). People with certain Mendelian disease variants that may be more susceptible to the impacts of environmental toxicants may therefore constitute a susceptible subpopulation of higher risk to be considered in regulations limiting exposures. Recently, an adverse outcome pathway (AOP) approach was proposed to potentially identify and integrate human genetic susceptibility in human health risk assessment (Mortensen et al., 2018). This methodology utilizes publicly available human genetic datasets to acquire mechanistic understanding of molecular pathways that might inform human susceptibility to an adverse outcome. This AOP-framed approach uses functional genomic and human polymorphism data to characterize individual and population-level genetic variation that may impact susceptibilities to environmental chemicals. The application of this approach may help to connect existing knowledge of both Mendelian and complex disease genetics to environmental toxicant susceptibility and further contribute to the understanding of the etiology of both monogenic and complex human disease outcomes.

A greater mechanistic understanding of the role of environmental exposures in Mendelian diseases may ultimately result in valuable public health translations. Recent focus on attempting to translate results of the genomic era into health benefits have shown limited value to date. Rather than focus on primarily genetic or pharmaceutical targets for intervention, current strategies need to also exploit environmental or behavioral modifications. Emphasis on precision medicine can incorporate environmental measures of human disease and utilize unique susceptibilities of individual patients based on their particular genetic makeup and past environmental exposures. Therapeutic or environmental interventions and preventions can then be tailored based on this knowledge (Groopman, 2019; Topol, 2014). Particularly in the absence of effective treatments to slow the course of Huntington’s and other classic Mendelian diseases, environmental interventions offer feasible approaches to delay disease onset or reduce the disease severity.