Research funded by grants
Systems approach points to mechanisms by which herbicide increases inflammatory bowel disease risk
Exposure to the herbicide propyzamide may increase inflammation in the intestine and the risk of inflammatory bowel disease (IBD), NIEHS-funded researchers found. The team developed a platform that combines publicly available databases, zebrafish and mouse studies, and machine learning to pinpoint environmental factors and mechanisms that drive IBD development. Read the full summary.
Citation: Sanmarco LM, Chao CC, Wang YC, Kenison JE, Li Z, Rone JM, Rejano-Gordillo CM, Polonio CM, et al. 2022. Identification of environmental factors that promote intestinal inflammation. Nature 611(7937):801–809.
Novel method can reduce use of animals in eye safety tests
NIEHS-funded researchers demonstrated that a nonanimal test can predict whether substances in consumer products cause eye damage. Called OptiSafe, the method can help researchers avoid using animals in eye safety tests. Read the full summary.
Citation: Lebrun S, Chavez S, Nguyen L, Chan R. 2022. Expansion of the application domain of a macromolecular ocular irritation test (OptiSafe). Toxicol In Vitro 86:105515.
New approach can predict autism diagnosis earlier in life
Researchers funded by NIH developed an approach to predict autism spectrum disorder (ASD) diagnosis earlier than current techniques. The tool, which uses information from an infant’s hair samples and machine-learning techniques, can enable more timely interventions for children with ASD. Read the full summary.
Citation: Austin C, Curtin P, Arora M, Reichenberg A, Curtin A, Iwai-Shimada M, Wright RO, Wright RJ, Remnelius KL, Isaksson J, Bölte S, Nakayama SF. 2022. Elemental dynamics in hair accurately predict future autism spectrum disorder diagnosis: an international multi-center study. J Clin Med 11(23):7154.
Paternal exposure to phthalates could have intergenerational effects on metabolic health
NIEHS-funded researchers found that paternal exposure to chemicals called phthalates may cause adverse metabolic health effects in two generations of offspring. The findings could improve understanding of how chemical exposures in parents contribute to chronic diseases in progeny, according to the team. Among various uses, phthalates add flexibility to plastic products and bring fragrance to personal care items. Read the full summary.
Citation: Liu J, Shi J, Hernandez R, Li X, Konchadi P, Miyake Y, Chen Q, Zhou T, Zhou C. 2023. Paternal phthalate exposure-elicited offspring metabolic disorders are associated with altered sperm small RNAs in mice. Environ Int 172:107769.
Nanoplastics cross through placenta from mother to fetus in vivo
Tiny plastic fragments ingested during pregnancy can cross the placenta to expose the unborn fetus, according to an NIEHS-funded study using rats. These miniscule pieces, collectively called micro- and nanoplastics (MNPs), appear throughout the environment and food web. Humans inadvertently consume MNPs in contaminated water or food. The findings demonstrate that ingested MNPs can traverse the intestinal and placental barriers to reach fetal circulation and tissues, according to the authors. Read the full summary.
Citation: Cary CM, DeLoid GM, Yang Z, Bitounis D, Polunas M, Goedken MJ, Buckley B, Cheatham B, Stapleton PA, Demokritou P. 2023. Ingested polystyrene nanospheres translocate to placenta and fetal tissues in pregnant rats: potential health implications. Nanomaterials (Basel) 13(4):720.
Air pollution may speed up bone loss in postmenopausal women
Elevated exposure to air pollution was associated with reduced bone density among postmenopausal women, NIEHS-funded scientists found. This research is the first to assess the effects of air pollution mixtures on bone health in women who have already undergone menopause. According to the authors, results confirmed that poor air quality may be a risk factor for bone loss and suggest that policies to reduce air pollution, especially nitrogen oxides, can help protect bone health among aging women. Read the full summary.
Citation: Prada D, Crandall CJ, Kupsco A, Kioumourtzoglou MA, Stewart JD, Liao D, Yanosky JD, Ramirez A, Wactawski-Wende J, Shen Y, Miller G, Ionita-Laza I, Whitsel EA, Baccarelli AA. 2023. Air pollution and decreased bone mineral density among Women's Health Initiative participants. EClinicalMedicine 57:101864.
New technology can remove PFAS from water
A small business funded by NIEHS developed a novel technology to clean up water contaminated with a group of chemicals known as PFAS. Their materials can be reused multiple times and are potentially less expensive than current remediation technologies, the authors said. PFAS have been detected in drinking water sources throughout the U.S. The small business plans to continue testing the most effective material's performance in the lab, as well as determining operational costs for its use in pilot projects and full-scale water treatment facilities. Read the full summary.
Citation: Singh A, Lynch R, Solomon J, Weaver JD, May AR. 2023. Development of novel fluor mop materials for remediation of perfluoroalkyl substances (PFAS) from groundwater. J Hazard Mater 448:130853.
Green space may reduce postpartum depression risk
Exposure to green space and increased physical activity may lower a mother’s risk of postpartum depression (PPD), NIEHS-funded researchers found. Approximately 13% of U.S. mothers experience PPD, which, if left untreated, can harm maternal health and may cause sleeping, eating, and behavioral problems for their babies. These findings may help inform policies and interventions aimed at increasing tree coverage to improve the benefits for maternal mental health, the team noted. Read the full summary.
Citation: Sun Y, Molitor J, Benmarhnia T, Avila C, Chiu V, Slezak J, Sacks DA, Chen J-C, Getahun D, Wu J. 2023. Association between urban green space and postpartum depression, and the role of physical activity: a retrospective cohort study in Southern California. Lancet Reg Health Am 21:100462.
Benefits of lower air pollution vary by racial identity and income
Black Americans of all incomes and White Americans with lower incomes may benefit more from reduced exposure to air pollution than affluent White Americans, according to an NIEHS-funded study. The results suggest that federal air quality regulations may insufficiently protect populations marginalized by race or socioeconomic class. In addition, the work suggests that lowering federally acceptable levels for fine particulate matter (PM2.5) would protect a wider array of older Americans. Read the full summary.
Citation: Josey KP, Delaney SW, Wu X, Nethery RC, DeSouza P, Braun D, Dominici F. 2023. Air pollution and mortality at the intersection of race and social class. N Engl J Med 388(15):1396–1404.
Disinfectant reduces toxic byproduct levels in algae-affected water
Adding the chemical chloramine, rather than the common disinfectant chlorine, to water contaminated by toxic algae can result in lower levels of harmful byproducts, an NIEHS-funded study found. Certain types of algae produce harmful chemicals that can taint drinking water supplies. In addition, water disinfection processes can interact with algae in other ways, resulting in hazardous byproducts that have been implicated in cancer, miscarriages, and other health problems. The results suggest that chloramine can be a superior disinfectant to chlorine in some cases, especially in waters that contain low concentrations of bromide and iodide. Read the full summary.
Citation: Aziz MT, Granger CO, Ferry JL, Richardson SD. 2023. Algae impacted drinking water: does switching to chloramination produce safer drinking water? Sci Total Environ 877:162815.
Mechanism linking PFAS exposure during pregnancy and early birth revealed
NIEHS-funded researchers identified molecular signatures of prenatal exposure to PFAS associated with early birth using a minimally invasive blood sampling technique. This study represents a significant step toward understanding how the pervasive chemicals may contribute to early term birth, a leading cause of infant death in the United States. Read the full summary.
Citation: Taibl KR, Dunlop AL, Barr DB, Li YY, Eick SM, Kannan K, Ryan PB, Schroder M, Rushing B, Fennell T, Chang CJ, Tan Y, Marsit CJ, Jones DP, Liang D. 2023. Newborn metabolomic signatures of maternal per- and polyfluoroalkyl substance exposure and reduced length of gestation. Nat Commun 14(1):3120.
Gut microbiome helps modulate social behavior and brain health in sex-specific ways
In mice, prenatal exposure to both air pollution and maternal stress led to male-specific deficits in social behavior and changes in the brain’s reward system, according to an NIEHS-funded study. The researchers also found that altering the offspring’s gut microbiome, or microbial composition, restored sociability. The findings suggest that the gut microbiome is an important modulator of both social behavior and specialized immune cells called microglia in males and could be a target for therapeutic interventions for autism, according to the authors. Read the full summary.
Citation: Smith CJ, Rendina DN, Kingsbury MA, Malacon KE, Nguyen DM, Tran JJ, Devlin BA, Raju RM, Clark MJ, Burgett L, Zhang JH, Cetinbas M, Sadreyev RI, Chen K, Iyer MS, Bilbo SD. 2023. Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system. Mol Psychiatry; 28(6):2549–2562.
Chemicals formed in well-done cooked meats may be risk factors for Parkinson’s
Exposure to compounds formed in red meat cooked at high temperatures may be a risk factor for Parkinson’s disease, NIEHS-funded scientists found. Research suggests that red meat may contribute to development of the disease; this study uncovered the potential mechanisms driving that relationship. Read the full summary.
Citation: Bellamri M, Brandt K, Cammerrer K, Syeda T, Turesky RJ, Cannon JR. 2023. Nuclear DNA and mitochondrial damage of the cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in human neuroblastoma cells. Chem Res Toxicol 36(8):1361–1373.
In-house research
The same toxic molecule underlies both a muscle disorder and absent nose
A protein called double homeobox 4 (DUX4) is not only responsible for a rare muscular disease but also kills the precursors of the human nose, according to NIEHS researchers and their collaborators. Moreover, the study implicates herpesviruses, which can cause sexually transmitted diseases, as potential environmental modifiers that may exacerbate DUX4 toxicity in cranial placode cells of the developing fetus. Read the full summary.
Citation: Inoue K, Bostan H, Browne MR, Bevis OF, Bortner CD, Moore SA, Stence AA, Martin NP, Chen SH, Burkholder AB, Li JL, Shaw ND. 2023. DUX4 double whammy: the transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose. Sci Adv 9(7):eabq7744.
How redox stress generates mutations
The metabolic and mutational signatures of different types of oxidizing agents vary widely, according to NIEHS researchers and their collaborators. Using a combination of genetic, biochemical, biophysical, and computational approaches, the researchers unexpectedly discovered distinct cellular metabolic landscapes and mutational motifs caused by exposure to potassium bromate compared to other redox agents. According to the authors, this study may provide the framework for identifying biomarkers of different types of redox stress in human tumors. Read the full summary and related article.
Citation: Degtyareva NP, Placentra VC, Gabel SA, Klimczak LJ, Gordenin DA, Wagner BA, Buettner GR, Mueller GA, Smirnova TI, Doetsch PW. 2023. Changes in metabolic landscapes shape divergent but distinct mutational signatures and cytotoxic consequences of redox stress. Nucleic Acids Res 51(10):5056– 5072.
Why breast cancer incidence varies across the United States
Environmental exposures and neighborhood-level socioeconomic factors may contribute to geographic disparities in breast cancer incidence, according to NIEHS researchers and their collaborators. Together, the results provide additional evidence for a role of environmental exposures in breast cancer incidence and suggest that geographic-based risk factors may vary according to breast cancer subtype. Read the full summary.
Citation: Carroll R, Ish JL, Sandler DP, White AJ, Zhao S. 2023. Understanding the role of environmental and socioeconomic factors in the geographic variation of breast cancer risk in the US-wide Sister Study. Environ Res 239(Pt 1):117349.
Assessing gene and protein regulation in children and adults with autoimmune disease
Analysis of gene regulation in patients with an autoimmune disorder called dermatomyositis has revealed potential therapeutic targets, according to NIEHS researchers and their collaborators. Dermatomyositis in adults and children affects skin and muscle tissues, causing rashes and weakness. Most gene regulation in these patients is described only at the level of transcripts — RNA molecules produced by copying a gene’s DNA sequence — with protein measurements limited to a targeted subset of genes of interest. No studies have previously analyzed transcript and protein expression together. Read the full summary.
Citation: Ward J, Ambatipudi M, O'Hanlon TP, Smith MA, de Los Reyes M, Schiffenbauer A, Rahman S, Zerrouki K, Miller FW, Sanjuan MA, Li J-L, Casey KA, Rider LG. 2023. Shared and distinctive transcriptomic and proteomic pathways in adult and juvenile dermatomyositis. Arthritis Rheumatol; doi: 10.1002/art.42615. [Online 25 May 2023].
Exploring the link between early-life trauma and diabetes
The association between traumatic childhood experiences and type 2 diabetes varies by race and ethnicity, according to NIEHS researchers and their collaborators. According to the authors, the study suggests that Latina women may be an understudied population at a particularly high risk of type 2 diabetes associated with early-life trauma. In addition, tailored prevention and intervention efforts that protect youth from trauma and inhibit likely mediators such as metabolic abnormalities may help ease the burden of type 2 diabetes among women. Read the full summary.
Citation: Gaston SA, Riley NM, Parks CG, Woo JMP, Sandler DP, Jackson CL. 2023. Racial/ethnic differences in associations between traumatic childhood experiences and both metabolic syndrome prevalence and type 2 diabetes mellitus risk among a cohort of US women. Diabetes Care 46(2):341–350.
Tracking trends in phthalate and phenol exposure during pregnancy
Pregnant women’s exposure to hormone-disrupting chemicals called phthalates and phenols have decreased over time, while exposure to phthalate replacements has increased, according to NIEHS researchers and their collaborators. In addition, biomarker concentrations of most chemical exposures were highest among non-Hispanic Black and Hispanic participants. According to the researchers, these findings highlight the importance of continued study of these new and emerging chemicals of concern. Read the full summary.
Citation: Bommarito PA, Stevens DR, Welch BM, Weller D, Meeker JD, Cantonwine DE, McElrath TF, Ferguson KK. 2023. Temporal trends and predictors of phthalate, phthalate replacement, and phenol biomarkers in the LIFECODES Fetal Growth Study. Environ Int 174:107898.
How disordered regions of proteins regulate RNA binding
Intrinsically disordered regions (IDRs) help to mediate interactions between partner proteins to control RNAs, according to NIEHS researchers and their collaborators. By determining a crystal structure of a roundworm protein called fem-3 binding factor-2 (FBF-2) and through biochemical studies, the researchers discovered that an IDR at the C-terminus of FBF-2 autoinhibits its RNA-binding affinity. The findings also suggest that LST-1 enhances FBF-2 RNA-binding affinity by displacing its C-terminus, thereby alleviating autoinhibition. Read the full summary.
Citation: Qiu C, Zhang Z, Wine RN, Campbell ZT, Zhang J, Hall TMT. 2023. Intra- and inter-molecular regulation by intrinsically-disordered regions governs PUF protein RNA binding. Nat Commun 14:7323.
How mice defend against bacteria
New research sheds light on the role of interferons in host defense that is mediated by a protein called Irgm1, according to NIEHS researchers and their collaborators. Taken together, the findings challenge the long-prevailing paradigm regarding how Irgm1 supports host defense. In particular, the results reveal an important role of a signaling molecule called type I interferon in this process, separate from the previously reported cell-intrinsic mechanism involving the protein interferon gamma. Read the full summary.
Citation: Rai P, Sharpe M, Ganta CK, Baker PJ, Mayer-Barber KD, Fee BE, Taylor GA, Fessler MB. 2023. IRGM1 supports host defense against intracellular bacteria through suppression of type I interferon in mice. J Clin Invest 133(21):e171982.
How long-term memories are created during sleep
A brain region called the entorhinal cortex (EC) plays a critical role in forming long-term memories during sleep by generating synchronous neural activity, according to NIEHS researchers and their collaborators. Together, the findings demonstrated that delta oscillations of temporoammonic pathway neurons are critical for the consolidation of newly encoded memory. Read the full summary.
Citation: Haam J, Gunin S, Wilson L, Fry S, Bernstein B, Thomson E, Noblet H, Cushman J, Yakel JL. 2023. Entorhinal cortical delta oscillations drive memory consolidation. Cell Rep 42(10):113267.
A protein called TRIM28 regulates uterine biology
Tripartite motif-containing 28 (TRIM28) is a protein that modulates steroid hormone signaling to regulate uterine function, according to NIEHS researchers and their collaborators. They found TRIM28 deficiency disrupted uterine cell functions and composition, leading to fertility defects through altered estrogen receptor-alpha (ER-alpha) and progesterone receptor (PR) action. In addition, TRIM28 deletion induced a gene signature resembling that of endometriosis — a condition in which cells typically found in the uterus grow outside the uterus. According to the authors, further study of TRIM28 modulation of ER-alpha and PR activity will provide critical insight for developing nonhormonal therapies for uterine diseases as well as obesity, immune disturbances, and muscular conditions. Read the full summary.
Citation: Li R, Wang T, Marquardt RM, Lydon JP, Wu SP, DeMayo FJ. 2023. TRIM28 modulates nuclear receptor signaling to regulate uterine function. Nat Commun 14(1):4605.
Uncovering an essential amino acid's unexpected effects on cancer
How the amino acid methionine affects cancer progression depends on the status of the immune system as well as gut microbes, according to NIEHS researchers and their collaborators. Methionine is a sulfur-containing essential amino acid and a key component of dietary proteins that is important for a variety of cellular functions. According to the authors, the study highlights a delicate balance of pro- and antitumor effects of dietary methionine and suggests that any possible anticancer benefits of methionine restriction require careful consideration of both the microbiota and the immune system. Read the full summary and related article.
Citation: Ji M, Xu X, Xu Q, Hsiao YC, Martin C, Ukraintseva S, Popov V, Arbeev KG, Randall TA, Wu X, Garcia-Peterson LM, Liu J, Xu X, Andrea Azcarate-Peril M, Wan Y, Yashin AI, Anantharaman K, Lu K, Li JL, Shats I, Li X. 2023. Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota. Nat Metab 5(9):1526–1543.
3D structures shed light on precursor step to protein production
New structural visualization of a protein complex known as TSEN shows how mutations may cause a family of human neurodevelopmental disorders, according to NIEHS researchers and their collaborators. In addition to providing insights into transfer RNAs recognition and processing, the findings revealed the structural environment of pontocerebellar hypoplasia-causing mutations, which suggests that loss of TSEN stability may contribute to neurodevelopmental disease. Read the full summary.
Citation: Hayne CK, Butay KJU, Stewart ZD, Krahn JM, Perera L, Williams JG, Petrovitch RM, Deterding LJ, Matera AG, Borgnia MJ, Stanley RE. 2023. Structural basis for pre-tRNA recognition and processing by the human tRNA splicing endonuclease complex. Nat Struct Mol Biol 30(6):824–833.
Division of Translational Toxicology research
How the most heavily used herbicide affects human cells
The herbicide glyphosate does not appear to pose a hazard to human DNA, according to researchers from the NIEHS Division of Translational Toxicology. Taken together, these results demonstrate that glyphosate does not produce DNA damage in the form of gene mutations, chromosome breaks, or changes in chromosome number, and that cytotoxicity (i.e., cell death) associated with glyphosate-based formulations may be related to other components of these formulations. For example, ingredients such as surfactants and detergents may compromise cell membranes or otherwise lead to cell death. Read the full summary.
Citation: Smith-Roe SL, Swartz CD, Rashid A, Christy NC, Sly JE, Chang X, Sipes NS, Shockley KR, Harris SF, McBride SJ, Larson GJ, Collins BJ, Mutlu E, Witt KL. 2023. Evaluation of the herbicide glyphosate, (aminomethyl)phosphonic acid, and glyphosate-based formulations for genotoxic activity using in vitro assays. Environ Mol Mutagen 64(4):202–233.
Expanding gene sequencing tool use in environmental carcinogen studies
A technique called whole exome sequencing (WES) has been successfully applied to rats to study how a fungal toxin may induce liver cancer, according to NIEHS researchers and their collaborators. According to the authors, the study demonstrates the validity of rat WES as an important molecular tool for use in investigative, translational studies that aim to shed light on the interplay among genetics, environmental influences, and disease biology. Read the full summary.
Citation: Foley JF, Elgart B, Phadke D, Mav D, Tripodi I, Clausen N, Weick M, Gladwell W, Gerrish K, Shah R, Merrick BA. 2023. Whole exome and transcript profiling of liver following aflatoxin B1 exposure in rats. J Appl Toxicol 43(9):1293–1305.
Streamlining toxicity testing in zebrafish
A new data analysis pipeline for assessing developmental toxicity outcomes using zebrafish could make comparing results across laboratories easier, according to researchers from the NIEHS Division of Translational Toxicology. According to the researchers, this is the first study to create tools for comparing zebrafish developmental toxicity results at the level of specific altered traits across laboratories. The study could pave the way for broader adoption of the zebrafish model for toxicological screening. Read the full summary.
Citation: Hsieh J-H, Nolte S, Hamm JT, Wang Z, Roberts GK, Schmitt CP, Ryan KR. 2023. Systematic Evaluation of the Application of Zebrafish in Toxicology (SEAZIT): developing a data analysis pipeline for the assessment of developmental toxicity with an interlaboratory study. Toxics 11(5):407.
Indoor wood-burning may be linked to lung cancer in U.S. women
Indoor wood-burning from stoves and fireplaces is associated with the development of lung cancer among women in the U.S., according to researchers from NIEHS, including the institute’s Division of Translational Toxicology. These findings are some of the first prospective evidence in the U.S. demonstrating that even occasional exposure to indoor wood smoke is associated with a higher incidence of lung cancer, including among never smokers. Read the full summary.
Citation: Mehta SS, Hodgson ME, Lunn RM, Ashley CE, Arroyave WD, Sandler DP, White AJ. 2023. Indoor wood-burning from stoves and fireplaces and incident lung cancer among Sister Study participants. Environ Int 178:108128.
How to evaluate endocrine-disrupting chemicals
The use of new approaches and new technologies may enhance the potential to detect effects when undertaking guideline-compliant rodent studies of suspected endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), according to a review article authored by researchers from the Division of Translational Toxicology. According to the authors, these insights and others detailed in the report may improve the sensitivity of future rodent toxicology studies to detect potential endocrine disruptors. Read the full summary.
Citation: Howdeshell KL, Beverly BEJ, Blain RB, Goldstone AE, Hartman PA, Lemeris CR, Newbold RR, Rooney AA, Bucher JR. 2023. Evaluating endocrine disrupting chemicals: a perspective on the novel assessments in CLARITY-BPA. Birth Defects Res 115(15):1345–1397.
