Research consortium identifies key characteristics of metabolic-disruptors

A team of NIEHS-funded researchers and collaborators developed a new approach to help risk assessors pinpoint chemicals that are likely to disrupt metabolism. The new method identifies key characteristics shared by chemicals with similar toxic effects.

Metabolic disruption can contribute to various diseases, including obesity, liver disease, and diabetes. While many environmental chemicals can disrupt metabolism, the underlying mechanisms are not well understood, and these effects have not been a major focus in chemical testing or risk assessments.

Building on previous work to identify key characteristics of carcinogenic chemicals, the research team reviewed scientific literature on metabolic disruption and identified important shared molecular changes that lead to toxicity. They defined 12 key characteristics of chemicals that disrupt metabolism, including altering the normal function of the pancreas, triggering insulin resistance, and promoting long-term inflammation and immune problems in metabolic tissues.

The researchers tested their approach by using environmental chemicals, infectious agents, and physical substances to demonstrate how the characteristics can help organize data to identify metabolism-disrupting chemicals. For example, tributyltin, an organic chemical used in ship paint to prevent marine growth, exhibited all 12 key characteristics. The authors suggest that identifying chemicals with multiple key characteristics, which indicates they may impact several important processes, can help prioritize the chemicals for further analysis.

According to the authors, this approach could aid in hazard identification, risk assessment, and chemical classification for metabolism-disrupting chemicals. Additionally, the key characteristics may help guide the development of assays to further study these chemicals. (MV)

Citation: 

La Merrill MA, Smith MT, McHale CM, Heindel JJ, Atlas E, Cave MC, Collier D, Guyton KZ, Koliwad S, Nadal A, Rhodes CJ, Sargis RM, Zeise L, Blumberg B. 2024. Consensus on the key characteristics of metabolism disruptors. Nat Rev Endocrinol; doi: 10.1038/s41574-024-01059-8 [Online ahead of print 29 Nov 2024].

Metal exposure linked to gut microbiome disruptions in children

A multi-omics study led by NIEHS-funded researchers uncovered a link between metal exposure and the gut microbiome in children. Multi-omics approaches combine analytical techniques from different biological fields to provide a more comprehensive understanding of health and disease.

Exposure to metals has been linked to various health issues in children, including effects on brain and body development. Disruptions to the gut microbiome, a diverse community of microorganisms in the gastrointestinal tract, may contribute to these conditions. However, the impact of metal exposure on the microbiome is not well understood.

Researchers analyzed stool samples from 116 children aged 8 to 12 years from Sherbrooke, Quebec, Canada. They measured metal concentrations within the children’s stool samples and applied a variety of multi-omics techniques, including shotgun metagenomic and metatranscriptomic analyses. These microbiome omics analyses look at both the species level taxonomy of gut microorganisms and the key biochemical processes, or functional pathways, carried out by these microbes.

Using statistical modeling, the researchers identified 23 links between metal concentrations in stool samples and specific gut microbiome species. For example, higher zinc levels were associated with higher relative abundance of Turicibacter sanguinis, microbes involved in lipid metabolism that are related to diseases like obesity and diabetes. Higher cadmium was linked to lower relative abundance of Eubacterium eligens, which also suggests the harmful effects of metals. The study also revealed that metal exposure altered 490 functional pathways in the gut, related to processes such as amino acid synthesis, carbohydrate breakdown, and energy production.

According to the authors, their findings reveal important connections between metal exposure, the gut microbiome, and potential health impacts, and support the need for further research to explore how these associations might influence childhood health. (MV)

Citation: 

Gao F, Shen Y, Wu H, Laue HE, Lau FK, Gillet V, Lai Y, Shrubsole MJ, Prada D, Zhang W, Liu Z, Bellenger JP, Takser L, Baccarelli AA. 2024. Associations of stool metal exposures with childhood gut microbiome multiomics profiles in a prospective birth cohort study. Environ Sci Technol 58(50):22053-22063.

Inhibiting inflammatory enzyme may protect against gut dysfunction caused by high-sugar diet

A study partially funded by NIEHS found that blocking a certain metabolic enzyme may alleviate inflammation caused by a high-sugar diet, offering potential benefits for some diet-related health issues. The findings also revealed the mechanisms behind organ damage caused by excessive sugar consumption. With the increasing sugar content of modern diets, this work may inform therapeutic interventions for health effects related to high sugar consumption, the authors noted.

The team first fed mice either a normal-sugar or high-sugar diet for 16 weeks. They then extracted the colons from the mice and measured markers related to gut health in the colon tissue. They found that mice fed a high-sugar diet had increased levels of inflammatory markers and decreased levels of anti-inflammatory markers in their gut. High-sugar diet mice also had lower levels of gut proteins that maintain the integrity of the intestinal lining, indicating damage to the gut barrier that prevents bacteria from leaking out of the intestines.

Then, the scientists used a technique called metabolomics to assess the genetic expression of certain proteins in the low-sugar and high-sugar diet mice. They found that levels of soluble epoxide hydrolase (sEH), an enzyme that breaks down fatty acids and is involved in inflammation, were elevated in high-sugar diet mice. When the team either used a chemical to block sEH or engineered sEH out, gut inflammation decreased in the high-sugar diet mice.

According to the authors, this study highlights sEH as a potential therapeutic target for gut dysfunction caused by high-sugar diets and provides valuable insights into how such diets harm gut health. (MZ) [See related article.]

Citation: 

Lin AZ, Fu X, Jiang Q, Zhou X, Hwang SH, Yin HH, Ni KD, Pan QJ, He X, Zhang LT, Meng YW, Liu YN, Hammock BD, Liu JY. 2024. Metabolomics reveals soluble epoxide hydrolase as a therapeutic target for high-sucrose diet-mediated gut barrier dysfunction. Proc Natl Acad Sci U S A 121(48):e2409841121.

Folic acid may help protect liver from prenatal chemical exposures

Treating folic acid and other vitamin B deficiencies during pregnancy may help prevent some negative effects of prenatal chemical exposure on children's liver health, according to a study funded by NIEHS. Additionally, the authors found that prenatal exposure to metabolism disruptors and other environmental chemicals may cause fat to accumulate around the liver, significantly impacting liver health for both mothers and their children.

The researchers studied 200 mother-child pairs from a pregnancy and birth study in Mexico. The team measured the levels of 43 metabolism-disrupting chemicals — including air pollutants, metals and metalloids, phthalates, and pesticides — during pregnancy, and analyzed liver enzymes from mothers and their children nine years after birth. They also examined how self-reported folic acid supplementation affected these results.

Statistical analysis revealed a link between exposure to metabolism-disrupting chemicals and an increased risk of liver injury and fat buildup in the liver, particularly in children. However, mothers who took folic acid supplements during pregnancy experienced a protective effect, with 600 micrograms daily associated with a reduced liver health risks for both mothers and their children. Higher maternal levels of cobalt — a key component of vitamin B12 — during pregnancy also had a protective effect.

According to the authors, these findings can help researchers design clinical interventions to address the growing epidemic of fatty liver diseases. (MZ) [See related article.]

Citation: 

India-Aldana S, Midya V, Betanzos-Robledo L, Yao M, Alcalá C, Andra SS, Arora M, Calafat AM, Chu J, Deierlein A, Estrada-Gutierrez G, Jagani R, Just AC, Kloog I, Landero J, Oulhote Y, Walker RW, Yelamanchili S, Baccarelli AA, Wright RO, Téllez Rojo MM, Colicino E, Cantoral A, Valvi D. 2024. Impact of metabolism-disrupting chemicals and folic acid supplementation on liver injury and steatosis in mother-child pairs. J Hepatol S0168-8278(24)02757-0.

Researchers rank chemicals with greatest potential to harm child brain health

NIEHS-funded researchers developed a ranked list of environmental chemicals with the potential to harm children’s neurological health. The resource, called the Environmental NeuRoactIve CHemicals (ENRICH) list, can help researchers more efficiently assess chemicals in biological samples, like blood or urine, which may adversely affect brain development and function.

For many chemicals, neurotoxicity data and biomonitoring data are scarce, especially for children. Biomonitoring data indicate the amount of chemicals present in a biological sample. The researchers set out to develop a prioritized list of neuroactive chemicals for biomonitoring and child neurotoxicity screening.

The team mined 11 databases to identify and rank chemicals based upon their likelihood of neuroactivity, detection in biological samples, experimental feasibility, and human exposure, especially early life exposure. They combined information across all databases, generating a list of 1,827 chemicals. The researchers further prioritized these substances, resulting in the ENRICH list of 250 top-ranking neuroactive chemicals for investigation. For these prioritized chemicals, the team considered potential sources of exposure and predicted which are likely to be excreted via urine, a biological sample commonly used in human studies. The ENRICH list included chemicals used in home maintenance, personal care products, cleaning products, vehicles, arts and crafts, and consumer electronics, among other sources.

The ENRICH resource represents a prioritized and experimentally feasible list of chemicals with high relevance to neurotoxicity and future biomonitoring efforts, especially in children. According to the authors, the list can enhance future cell, animal, and human studies evaluating the potential effects of environmental chemicals on neural health. (MA)

Citation: 

Rager JE, Koval LE, Hickman E, Ring C, Teitelbaum T, Cohen T, Fragola G, Zylka MJ, Engel LS, Lu K, Engel SM. 2025. The environmental neuroactive chemicals list of prioritized substances for human biomonitoring and neurotoxicity testing: a database and high-throughput toxicokinetics approach. Environ Res 266:120537.

Large floods linked to increased death rates for several causes

Large flooding events in the United States may increase death rates for cardiovascular diseases, infectious diseases, and injuries, among other causes of death, according to NIEHS-funded scientists. Although flooding has been linked to a range of adverse health outcomes, this study is the first to comprehensively examine mortality following floods.

The study included 35.6 million complete death records and flood exposure data from every county in the continental U.S. that experienced a large flood event from 2001 to 2018. The team estimated the relationship between flooding and death rates for six major causes — cancers, cardiovascular diseases, infectious and parasitic diseases, injuries, neuropsychiatric conditions, and respiratory diseases — at the county level. They assessed associations up to three months after the flood and considered the effects of age, sex, and flood cause.

During the 18-year study period, 93 large flood events occurred. Heavy rain was the most common cause of flooding, followed by tropical cyclone-related flooding. During the month of a severe rain-related flood, death rates for infectious disease and cardiovascular disease increased by 3.2% and 2.1%, respectively. During the month of a tropical cyclone-related flood, there was a 15.3% rise in injury death rates. For tropical cyclone-related floods, the injury death rate was higher for those 65 years or older than for younger individuals and for females compared with males.

According to the authors, the study findings provide information that could help public health agencies allocate resources and better prepare for severe flood events. [See related article.] (MA)

Citation: 

Lynch VD, Sullivan JA, Flores AB, Xie X, Aggarwal S, Nethery RC, Kioumourtzoglou M-A, Nigra AE, Parks RM. 2025. Large floods drive changes in cause-specific mortality in the United States. Nat Med 31(2):663-671.

Exposure mixtures linked to health effects in 9/11 World Trade Center responders

The mixture of exposures experienced by responders to the 9/11 World Trade Center (WTC) attacks may have contributed to a range of diseases and mental health conditions, according to a study by NIEHS-funded researchers. This study is the first to examine the WTC exposome, which is the combined effects of all exposures encountered during the rescue and recovery effort, on workers’ health.

The study included data from nearly 35,000 participants enrolled in the WTC Health Program General Responder Cohort. At a post-9/11 baseline visit, responders completed questionnaires on exposure history, sociodemographic characteristics, medical conditions, and mental health symptoms. The researchers generated a WTC exposome index made up of chemical and nonchemical factors collected during the baseline visit. Using advanced statistical methods, they assessed associations between the WTC exposome and post-traumatic stress disorder, gastroesophageal reflux disease, respiratory problems, diabetes, and headaches.

Exposure to harmful substances and hazardous conditions, as reflected in the WTC exposome index, was linked with all investigated health outcomes. Risk factors for these conditions included working in an enclosed area heavily contaminated with dust and debris, as well as exposure to blood and body fluids during rescue and recovery efforts. Conversely, being employed full-time protected against some health conditions.

According to the authors, this study emphasizes the importance of considering mixtures of exposures to inform interventions that will support the health and well-being of disaster response workers. (MA)

Citation: 

Rechtman E, Rodriguez MA, Colicino E, Hahn CJ, Navarro E, Invernizzi A, Dasaro CR, Teitelbaum SL, Todd AC, Horton MK. 2024. The World Trade Center exposome and health effects in 9/11 rescue and recovery workers. Commun Med (Lond) 4(1):257.

Artificial intelligence facilitates pollution reporting

NIEHS-funded researchers created an artificial intelligence (AI) chatbot that allows communities to report pollution incidents through a simple text messaging platform.

Community members are often the first to notice pollution events, but reporting their concerns to the appropriate organizations can be challenging. To overcome barriers, the team built an AI application that uses a large language model to communicate with users in a conversational manner. Such a chatbot can guide users through the reporting process by collecting, validating, and submitting data to the proper organizations.

To test the prototype, university faculty, staff, and students engaged in 346 conversations with the chatbot. On average, the user and chatbot exchanged 15 messages per conversation. The team found that the chatbot was customizable to a variety of use cases and guided users through the formal reporting process by asking relevant questions and gathering necessary information in a conversational manner. The application stored structured data that can be formally submitted to appropriate authorities, such as the North Carolina Department of Environmental Quality.

According to the team, this strategy highlights the potential of AI and large language models to create user-friendly tools that help communities translate environmental health concerns into actionable information for reporting to the relevant organizations. (MA)

Citation: 

Chiu WA, Newman G, Sansom G, Ye X, Rusyn A, Wu H, Winckelman T, Rusyn I. 2025. MyEcoReporter: a prototype for artificial intelligence-facilitated pollution reporting. J Expo Sci Environ Epidemiol; doi: 10.1038/s41370-025-00747-5. [Online ahead of print 20 Jan 2025].