Leveraging geospatial exposure models to enhance public health

A recent review led by researchers from the Division of Translational Toxicology provides new insights about geospatial exposure modeling methods that are otherwise scattered across a vast literature.

Geospatial methods are common in environmental exposure assessments and are an important tool for understanding complex environmental impacts on human health. However, the vast literature makes comparisons of these exposure methods and health applications difficult. By conducting a literature review and synthesis, the authors systematically evaluated geospatial exposure models and approaches for health data integration in environmental health applications.

The analysis revealed key concepts and terminology for geospatial exposure data and models and provided an overview of workflows in geospatial exposure model development and health data integration. In addition, the authors reviewed modeling approaches across diverse exposure types, such as air quality, water quality, climate, and socioeconomic factors. For each model type, they provided descriptions, general equations, and example applications for environmental exposure assessment.

Moreover, the authors discussed approaches used to integrate geospatial exposure data and health data, such as methods to link data sources with disparate spatial and temporal scales. The review article also covered the landscape of open-source tools supporting these workflows. According to the authors, geospatial exposure modeling can advance our understanding of the environmental determinants of health and promote evidence-based interventions to improve public health. (JW)

Citation: Clark LP, Zilber D, Schmitt C, Fargo DC, Reif DM, Motsinger-Reif AA, Messier KP. 2024. A review of geospatial exposure models and approaches for health data integration. J Expo Sci Environ Epidemiol 10.1038/s41370-024-00712-8. Epub 6 Sept.

Estrogen and progesterone act together to control uterine gene expression

The hormones estrogen and progesterone regulate gene expression differently during two stages of the mouse reproductive cycle, according to NIEHS researchers. The findings could enhance the understanding of how hormone regulation of genes contributes to both health and disease.

The hormones estrogen and progesterone play critical roles in regulating the female reproductive cycle at the molecular level. Estrogen usually triggers cellular growth, whereas progesterone induces cellular differentiation. These hormones cause such changes by binding to DNA and turning genes on or off, a process known as gene expression. However, the mechanics of how estrogen and progesterone regulate gene expression in adult female mice are incompletely understood. In this study, researchers studied these dynamics during the rodent reproductive cycle, which is called the estrous cycle.

The research team examined how estrogen and progesterone regulate uterine gene expression in mice during two stages of the estrous cycle: diestrus, when estrogen levels are highest, and estrus, when progesterone levels are highest. They found that the receptors of both estrogen and progesterone associated together as a complex during diestrus and bind to DNA to cause gene expression changes but then lose association with each other and the DNA during estrus. Some gene regions became more accessible during diestrus, allowing the complex to bind and regulate gene expression. Binding of other molecules independent of the hormone receptors, such as the transcription factor HIF2A, may also play a key role in regulating gene expression.

Future studies of the estrogen and progesterone receptor complex and the accessibility of DNA will be important for more fully understanding the gene expression changes occurring during the reproductive cycle. (BS)

Citation: Jefferson WN, Wang T, Padilla-Banks E, Williams CJ. 2024. Unexpected nuclear hormone receptor and chromatin dynamics regulate estrous cycle dependent gene expression. Nucleic Acids Res 10.1093/nar/gkae714. Epub 21 Aug.

Molecular structure may hold promise for treating mitochondrial diseases

Insights into the high-resolution structure of molecules called mtSSB and ssDNA may lead to new therapies for mitochondrial diseases, according to NIEHS researchers.

The mitochondrial single-stranded DNA (ssDNA) binding protein (mtSSB) is encoded by the SSBP1 gene. mtSSB is a crucial component in DNA replication, maintenance, and repair of the mitochondrial genome. Clinical mutations in the SSBP1 gene have been linked to a range of mitochondrial disorders affecting nearly all organs and systems. Yet, the molecular determinants governing the interaction between mtSSB and ssDNA have remained elusive. Similarly, the structural interaction between mtSSB and the mitochondrial DNA polymerase, Polγ, has been minimally explored.

To address this knowledge gap, the researchers determined a high-resolution X-ray crystallography structure of the human mtSSB bound to ssDNA. This structure uncovered two distinct DNA binding sites: a low-affinity site and a high-affinity site. The high-affinity binding site encompasses an amino acid residue, R38, which is mutated in mitochondrial diseases. Using cryogenic electron microscopy, the researchers also began to resolve the interaction surface of mtSSB and Polγ.

According to the authors, the identification and characterization of SSBP1 mutations is crucial for the diagnosis and management of mitochondrial diseases, and further research into the mechanisms underlying these mutations could lead to the development of novel therapies. (JW)

Citation: Riccio AA, Bouvette J, Pedersen LC, Somai S, Dutcher RC, Borgnia MJ, Copeland WC. 2024. Structures of the mitochondrial single-stranded DNA binding protein with DNA and DNA polymerase γ. Nucleic Acids Res 52(17):10329-340.

An enhancer RNA may hold potential for neurodegenerative diseases

A molecule called APOE-activating noncoding RNA (AANCR) is a key enhancer RNA in some cell types within the nervous system, according to NIEHS researchers and their collaborators.

Enhancers — critical regulatory elements within the human genome — are often transcribed into enhancer RNAs. The dysregulation of enhancers leads to diseases collectively termed enhanceropathies. Although it is known that enhancers play a role in diseases by regulating gene expression, the specific mechanisms by which individual enhancers cause diseases are not well understood.

To fill this knowledge gap, the researchers examined the role of AANCR in the central nervous system. The results showed that AANCR transcripts are crucial for promoting the expression of APOE, which is a gene known to be associated with Alzheimer's disease. Once activated, AANCR enhances APOE expression, which, in turn, leads to an inflammatory response in non-neuronal cells called astrocytes.

According to the authors, these findings demonstrate that AANCR is pivotal for regulating APOE expression and influencing inflammatory responses, underscoring its potential as a therapeutic target in neurodegenerative diseases. Future investigation into altering AANCR or APOE expression is warranted to examine the potential to modulate inflammation. In addition, the authors suggest that elucidating the nucleic acid biology of enhancers may lead to better therapeutic options for enhanceropathies. (JW)

Citation: Wan M, Liu Y, Li D, Snyder RJ, Elkin LB, Day CR, Rodriguez J, Grunseich C, Mahley RW, Watts JA, Cheung VG. 2024. The enhancer RNA, AANCR, regulates APOE expression in astrocytes and microglia. Nucleic Acids Res 52(17):10235-254.

Environmental phenol exposure may affect fetal growth and development

Prenatal exposure to environmental phenols may alter fetal growth and could potentially lead to downstream health consequences, according to NIEHS researchers and their collaborators.

Environmental phenols are endocrine-disrupting chemicals that are commonly used in personal care and consumer products, including sunscreens, food packaging, and children’s toys. Endocrine-disrupting chemicals can perturb hormonal functions, resulting in adverse health outcomes, such as impaired reproductive development. Previous studies have primarily evaluated associations between phenol exposure and fetal growth using delivery measures, particularly birthweight. Although birthweight continues to be a clinically relevant measure of fetal growth, this method does not examine the dynamic changes in growth that occur across pregnancy.

To overcome this limitation, the researchers incorporated ultrasound measures of fetal growth into their study. Their analysis involved 900 participants from the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort study of babies born at the small, appropriate, and large ends of the growth spectrum. The authors evaluated the levels of 12 urinary phenol biomarkers and used both ultrasound and birthweight to assess fetal growth.

The researchers found a strong and consistent association between prenatal exposure to 2,4-dichlorophenol, benzophenone-3, and triclosan and an increase in fetal growth. However, these associations were not found to be significant at the time of delivery. A consistent association remained between triclosan exposure and birthweight. In addition, the phenol biomarker methylparaben was associated with an increased risk of having babies who are born small for gestational age.

Together, the results contribute to the current evidence indicating that environmental phenol exposure during pregnancy may affect fetal growth and development. According to the authors, further research is warranted to assess potential long-term health effects of environmental phenol exposure during pregnancy. (SS)

Citation: Bommarito PA, Stevens DR, Welch BM, Meeker JD, Cantonwine DE, McElrath TF, Ferguson KK. 2024. Prenatal exposure to environmental phenols and fetal growth across pregnancy in the LIFECODES fetal growth study. Environ Int 190:108866.