Research funded by grants

Metals from e-cigarette aerosols accumulate in the brain

Mice exposed to e-cigarette aerosols had a buildup of toxic metals in the brain, according to NIEHS-funded researchers. The exposure also altered brain levels of essential metals, which play a key role in many biological processes. The findings provide clues about the onset of neurodegenerative diseases, which have been linked to toxic metal exposure and the dysregulation of essential metals.

The researchers exposed mice to either the equivalent of secondhand e-cigarette aerosol or a five-fold higher level for two months. They then measured levels of 15 different metals in brain and other central nervous system (CNS) tissues, such as the spinal cord.

Compared with unexposed mice, mice exposed to e-cigarette aerosol had significant buildup of several metals in the brain and CNS. Many of the metals that accumulated in exposed mice were known neurotoxins, including chromium, copper, iron, and lead.

Citation: Re DB, Hilpert M, Saglimbeni B, Strait M, Ilievski V, Coady M, Talayero M, Wilmsen K, Chesnais H, Balac O, Glabonjat RA, Slavkovich V, Yan B, Graziano J, Navas-Acien A, Kleiman NJ. 2021. Exposure to e-cigarette aerosol over two months induces accumulation of neurotoxic metals and alteration of essential metals in mouse brain. Environ Res 202:111557. (Synopsis(https://factor.niehs.nih.gov/2021/9/papers/dert/#a1))

Promising therapy for fatal sickle cell disease complication

An NIEHS-funded study in mice showed how chlorine exposure leads to acute chest syndrome, a leading cause of death in patients with sickle cell disease (SCD). The results point to a potential lifesaving therapy for SCD patients exposed to chlorine, which is found in some household cleaning products.

The researchers used genetically engineered mice that resembled SCD in humans (sickle mice) and compared them with healthy control mice with human hemoglobin. They exposed both groups to chlorine gas or normal air.

Within six hours of chlorine exposure, 64% of sickle mice died, whereas none of the controls died. Compared with controls, surviving sickle mice experienced lung injury and hemolysis, or the rupture of red blood cells, which releases hemoglobin into the blood. Hemopexin treatment following exposure significantly improved survival and reduced blood heme levels and lung injury.

Citation: Alishlash AS, Sapkota M, Ahmad I, Maclin K, Ahmed NA, Molyvdas A, Doran S, Albert CJ, Aggarwal S, Ford DA, Ambalavanan N, Jilling T, Matalon S. 2021. Chlorine inhalation induces acute chest syndrome in humanized sickle cell mouse model and ameliorated by postexposure hemopexin. Redox Biol 44:102009. (Synopsis(https://factor.niehs.nih.gov/2021/8/papers/dert/#a1))

Higher temperatures linked to lower ovarian reserve

Women exposed to higher temperatures had a lower ovarian reserve, according to NIEHS-funded researchers. Ovarian reserve refers to the number and quality of a woman’s eggs. A diminished ovarian reserve reduces a woman’s ability to get pregnant.

The study included 631 women aged 18-45 years enrolled in a reproductive health study in Massachusetts. Using each woman’s home address, the researchers estimated daily ambient temperature exposures for three months, one month, and two weeks before the ovarian reserve examination. They used ultrasonography to measure antral follicle count (AFC), a measure of ovarian reserve.

Exposure to higher temperatures was associated with a lower AFC. The negative association between temperature and AFC was stronger in November through June compared with the summer months. The finding suggests women may be more susceptible to heat during certain times of the year, potentially because they adapt to heat in the summer.

Citation: Gaskins AJ, Minguez-Alarcon L, VoPham T, Hart JE, Chavarro JE, Schwartz J, Souter I, Laden F. 2021. Impact of ambient temperature on ovarian reserve. Fertil Steril 116(4):1052–1060. (Synopsis(https://factor.niehs.nih.gov/2021/8/papers/dert/#a2))

Gene atlas provides insight into breast cancer origin

NIEHS grantees developed a gene expression atlas that captures the cellular makeup of the mammary gland across life stages, providing clues on how breast cancer originates. To build the atlas, the researchers used single cell RNA sequencing data, which assesses gene and protein expression of an individual cell. They integrated data from 50,000 mouse mammary cells, covering eight life stages, and 24,000 adult human mammary cells.

Using known genetic markers, team members identified the clusters as three breast epithelial cell types. The scientists compared genetic profiles for each epithelial cell type with known cancer-related genes to infer breast cancer cells of origin. They also examined how reorganization during different life stages altered breast cellular makeup and breast cancer subtype risk. According to the authors, the atlas provides insights into cellular makeup and development of breast cancer subtypes.

Citation: Saeki K, Chang G, Kanaya N, Wu X, Wang J, Bernal L, Ha D, Neuhausen SL, Chen S. 2021. Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis. Commun Biol 4(1):660. (Synopsis(https://factor.niehs.nih.gov/2021/8/papers/dert/#a3))

Childhood lead exposure affects midlife brain

Children exposed to lead have altered brain structure and poorer cognitive function in midlife, according to NIEHS-funded research. These lead-related brain changes may increase the risk of neurodegenerative disease, like dementia, in later life.

The study included 564 children who were enrolled in a New Zealand birth cohort in the early 1970s and followed to midlife. The researchers measured child blood lead levels at age 11 years. Using magnetic resonance imaging, they examined participants’ structural brain integrity at age 45 years. They also assessed adult cognitive function and intelligence using a standardized IQ test.

Higher lead exposure in childhood was associated with structural deficits in the middle-aged brain. The results suggest that adults exposed to lead as children may be at increased risk of neurodegenerative diseases in later life and reinforce the need for long-term follow-up of lead-exposed child cohorts.

Citation: Reuben A, Elliott ML, Abraham WC, Broadbent J, Houts RM, Ireland D, Knodt AR, Poulton R, Ramrakha S, Hariri AR, Caspi A, Moffitt TE. 2020. Association of childhood lead exposure with MRI measurements of structural brain integrity in midlife. JAMA 324(19):1970–1979. (Synopsis(https://factor.niehs.nih.gov/2021/1/papers/dert/#a2))

Children’s gut microbiome linked with household chemical exposure

Exposure to semi-volatile organic compounds (SVOCs) was linked with changes to young children’s gut microbiome, according to a new NIEHS-funded study. SVOCs are common contaminants of indoor air and dust.

The researchers measured levels of 44 SVOCs, including phthalates and per- and polyfluoroalkyl substances (PFAS), in the blood and urine of 69 children aged 3 to 6 years. Using genetic sequencing techniques, they determined the types and abundance of bacteria and fungi present in child stool samples.

Children with higher levels of PFAS in their blood had a lower number and diversity of bacteria in their gut. Higher phthalate levels were associated with a reduction in gut fungal populations. Surprisingly, children with higher levels of certain SVOCs, including triclosan, had several types of bacteria in their gut known to break down toxic chemicals in the environment.

Citation: Gardner CM, Hoffman K, Stapleton HM, Gunsch CK. 2021. Exposures to semivolatile organic compounds in indoor environments and associations with the gut microbiomes of children. Environ Sci Technol Lett 8(1):73−79. (Synopsis(https://factor.niehs.nih.gov/2021/1/papers/dert/#a4))

Chemicals in consumer products increase hormones, breast cancer risk

A new NIEHS-funded study showed that exposure to nearly 300 common chemicals can cause cells to produce more estrogen or progesterone, which may increase breast cancer risk.

The study included data for more than 650 chemicals tested in the U.S. Environmental Protection Agency’s ToxCast program. The researchers examined the data to identify chemicals that increased progesterone or estradiol, a form of estrogen, in a human cancer cell line.

Of the chemicals tested, 296 increased estradiol or progesterone in cells, whereas 71 chemicals increased both hormones. Using data from existing animal studies, the researchers then classified the hormone-increasing chemicals as either likely or unlikely to cause cancer or result in poor reproductive or developmental outcomes. Thirty percent were classified as likely carcinogens or reproductive or developmental toxicants, whereas only 5%-13% were classified as unlikely to cause these health outcomes.

Citation: Cardona B, Rudel RA. 2021. Application of an in vitro assay to identify chemicals that increase estradiol and progesterone synthesis and are potential breast cancer risk factors. Environ Health Perspect 129(7):77003. (Synopsis(https://factor.niehs.nih.gov/2021/9/papers/dert/#a2))

New insights into how COVID-19 may damage the heart

A study by NIEHS-funded researchers provides insight into how SARS-CoV-2, the virus that causes COVID-19, damages heart cells. The findings may inform treatment strategies to protect heart health in COVID-19 patients.

Using stem cells, the researchers created three types of human heart cells — cardiomyocytes, cardiac fibroblasts, and endothelial cells — and exposed them to small amounts of the SARS-CoV-2 virus for 48 hours. The virus was only able to infect and replicate in cardiomyocytes, the heart muscle cells. Unlike the other cell types, cardiomyocytes had ACE2 receptors on their surface, which serve as the cellular entry point for the virus.

Infected cardiomyocytes showed structural defects and had decreased expression of genes important in heart contraction. Many cardiomyocytes were missing nuclear DNA. Without this DNA, cells cannot function. Heart tissue samples from deceased COVID-19 patients mirrored the structural and genetic changes observed in cell models.

Citation: Perez-Bermejo JA, Kang S, Rockwood SJ, Simoneau CR, Joy DA, Silva AC, Ramadoss GN, Flanigan WR, Fozouni P, Li H, Chen PY, Nakamura K, Whitman JD, Hanson PJ, McManus BM, Ott M, Conklin BR, McDevitt TC. 2021. SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19. Sci Transl Med 13(590):eabf7872. (Synopsis(https://factor.niehs.nih.gov/2021/7/papers/dert/#a2))

Biomarkers during pregnancy point to early autism diagnosis

Using machine learning, NIEHS-funded researchers identified patterns in maternal autoantibodies, immune proteins that attack a person’s own proteins or tissues, that were highly associated with the diagnosis and severity of autism spectrum disorder (ASD).

The team previously identified maternal autoantibodies against eight key proteins related to ASD. In this study, the researchers developed an accurate test for reactivity patterns against those proteins that could predict ASD. They analyzed plasma samples from 450 mothers of children with autism and 342 mothers of typically developing children from the Childhood Autism Risks from Genetics and Environment (CHARGE) study.

The researchers found autoantibody reactivity to a single protein did not correlate with ASD diagnosis. Instead, reactivity to autoantibodies to CRIMP1 combined with any of the top proteins increased the likelihood of a higher ASD severity score. The approach may aid early ASD detection, which can help facilitate early interventions.

Citation: Ramirez-Celis A, Becker M, Nuno M, Schauer J, Aghaeepour N, Van de Water J. 2021. Risk assessment analysis for maternal autoantibody-related autism (MAR-ASD): a subtype of autism. Mol Psychiatry 26(5):1551–1560. (Synopsis(https://factor.niehs.nih.gov/2021/3/papers/dert/#a1))

Prenatal phthalate exposure may affect children’s executive function

Elevated levels of phthalates during pregnancy may negatively affect executive function in children, according to an NIEHS-funded study. Executive function — a set of complex cognitive skills, such as emotional regulation, impulse control, working memory, and attentional flexibility — enables people to focus, follow directions, and handle emotions.

Researchers measured 12 phthalate metabolites in urine samples collected at 17 weeks of pregnancy. Among those children sampled, born between 2003 and 2008, the researchers compared 262 children who had attention-deficit hyperactivity disorder symptoms with 78 typically developing children.

Exposure to higher levels of mono-benzyl phthalate (MBzP) in maternal urine during the prenatal period was associated with poorer executive function in both sexes. Also, higher levels of mono-n-butyl phthalate and mono-iso-butyl phthalate affected executive function, but results varied by evaluation method. For example, inhibition reported by parents was most affected by both chemicals, with stronger associations among boys.

Citation: Choi G, Villanger GD, Drover SSM, Sakhi AK, Thomsen C, Nethery RC, Zeiner P, Knudsen GP, Reichborn-Kjennerud T, Overgaard KR, Herring AH, Skogan AH, Biele G, Aase H, Engel SM. 2021. Prenatal phthalate exposures and executive function in preschool children. Environ Int 149:106403. (Synopsis(https://factor.niehs.nih.gov/2021/5/papers/dert/#a2))

Hospitalization following extreme weather, opportunities for resilience

NIEHS-funded researchers observed an increase in respiratory disease and other hospitalizations among older adults following exposure to tropical cyclones, which may help hospitals become better prepared in the future. Tropical cyclone is a generic term used to describe tropical depressions, tropical storms, and hurricanes.

The team used data on 70 million Medicare hospitalizations for individuals 65 years and older and a comprehensive database of county-level local winds to estimate tropical cyclone exposures between 1999 and 2014. Using advanced statistical models, they examined how tropical cyclone exposure related to hospitalizations for 13 different causes.

In the week following tropical cyclone exposure, researchers observed an average increase in hospitalizations from several causes, including respiratory diseases, infectious and parasitic diseases, and injuries. The results demonstrate the need for targeted hospital preparedness strategies before, during, and after tropical cyclones and other extreme weather.

Citation: Parks RM, Anderson GB, Nethery RC, Navas-Acien A, Dominici F, Kioumourtzoglou MA. 2021. Tropical cyclone exposure is associated with increased hospitalization rates in older adults. Nat Commun 12(1):1545. (Synopsis(https://factor.niehs.nih.gov/2021/5/papers/dert/#a3))

Air cleaners may improve COPD

Portable air cleaners may improve respiratory symptoms among former smokers with chronic obstructive pulmonary disease (COPD), according to an NIEHS-funded study. COPD is a progressive disease characterized by lung injury and inflammation and has limited treatment options.

Smoking cessation can slow the advancement of COPD, but former smokers continue to be affected by the disease, which can be worsened by exposure to air pollutants, such as particulate matter and nitrogen dioxide. The team conducted a blinded, randomized controlled trial of 116 former smokers with moderate to severe COPD. Participants received active or sham portable HEPA air cleaners for their homes and were followed for six months.

The active HEPA filter group experienced reduced respiratory symptoms and fewer urgent health care visits compared with the sham group. They also had lower rates of systemic steroid, antibiotic, or rescue medication use.

Citation: Hansel NN, Putcha N, Woo H, Peng R, Diette GB, Fawzy A, Wise RA, Romero K, Davis MF, Rule AM, Eakin MN, Breysse PN, McCormack MC, Koehler K. 2021. Randomized clinical trial of air cleaners to improve indoor air quality and COPD health: results of the CLEAN AIR STUDY. Am J Respir Crit Care Med; doi:10.1164/rccm.202103-0604OC [Online 27 August 2021]. (Synopsis(https://factor.niehs.nih.gov/2021/11/papers/dert/#a1))

Pancreatic cancer signatures point to early detection, new treatments

An international team of researchers, funded in part by NIEHS, identified promising new targets for treatment and early diagnosis of pancreatic ductal adenocarcinoma (PDAC), a highly aggressive condition with poor patient survival.

Using samples from 140 pancreatic cancers and more than 70 normal pancreatic tissues, the scientists carried out genomic, RNA, and microRNA sequencing, combined with detailed analyses of protein modifications. Focusing on 222 proteins that were at least twice as abundant in cancerous cells than in normal cells, they identified 12 proteins that they say could aid early detection in blood samples.

They also found nearly 5,000 sites within these proteins with increased phosphate groups and more than 1,700 sites with increased carbohydrate chains. The team said several of these patterns offered clues for treatment, such as blocking the enzymes involved in specific protein modifications associated with PDAC.

Citation: Cao L, Huang C, Cui Zhou D, Hu Y, Lih TM, Savage SR, Krug K, Clark DJ, Schnaubelt M, Chen L, da Veiga Leprevost F, Eguez RV, Yang W, Pan J, Wen B, Dou Y, Jiang W, Liao Y, Shi Z, Terekhanova NV, Cao S, Lu RJ, Li Y, Liu R, Zhu H, Ronning P, Wu Y, Wyczalkowski MA, Easwaran H, Danilova L, Mer AS, Yoo S, Wang JM, Liu W, Haibe-Kains B, Thiagarajan M, Jewell SD, Hostetter G, Newton CJ, Li QK, Roehrl MH, Fenyö D, Wang P, Nesvizhskii AI, Mani DR, Omenn GS, Boja ES, Mesri M, Robles AI, Rodriguez H, Bathe OF, Chan DW, Hruban RH, Ding L, Zhang B, Zhang H; Clinical Proteomic Tumor Analysis Consortium. 2021. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell 184(19):5031–5052.e26. (Synopsis(https://factor.niehs.nih.gov/2021/11/papers/dert/#a3))

Plant leaves work as reliable air monitor in citizen-science study

Working with citizen-scientists, NIEHS-funded researchers demonstrated that leaves can be used as a low-cost, reliable method to assess the level of metals in airborne dust. The method can help assess exposure from former mine sites that emit heavy metals that can be distributed by wind to nearby communities.

Twenty participants from Superior, Arizona, placed a potted peppermint plant and disc sampler in a self-selected area, usually outside of their home. After one month, they submitted two leaves and the disc for analysis of seven different metals — arsenic, lead, cadmium, copper, aluminum, nickel, and zinc.

On both the leaves and discs, levels of all metals decreased as distance from the mine increased. The results suggest that plant leaves can serve as a reliable monitor of metal-laden aerosols and that the low-cost technique is applicable to sites where resources are limited.

Citation: Zeider K, Van Overmeiren N, Rine KP, Sandhaus S, Eduardo Saez A, Sorooshian A, Munoz HC Sr, Ramirez-Andreotta MD. 2021. Foliar surfaces as dust and aerosol pollution monitors: an assessment by a mining site. Sci Total Environ 790:148164. (Synopsis(https://factor.niehs.nih.gov/2021/10/papers/dert/#a2))

Wildfire smoke linked to increase in COVID-19 cases and deaths

Thousands of COVID-19 cases and deaths in the western U.S. may be attributable to increases in fine particulate matter air pollution (PM2.5) from wildfires, according to NIEHS-funded research. Exposure to wildfire smoke can increase the risk of lung infections, including COVID-19.

The researchers linked publicly available data on daily PM2.5 levels and the number of COVID-19 cases and deaths that occurred between March and December 2020 in 92 counties across California, Oregon, and Washington. They developed a model to estimate the association between daily changes in PM2.5 and percentage increase in COVID-19 cases and deaths up to 28 days after exposure.

From August to October 2020, when fire activity was greatest, daily levels of PM2.5 during wildfire days were significantly higher than on non-wildfire days. The total number of COVID-19 cases and deaths attributable to daily increases in PM2.5 from wildfires were 19,742 and 748, respectively.

Citation: Zhou X, Josey K, Kamareddine L, Caine MC, Liu T, Mickley LJ, Cooper M, Dominici F. 2021. Excess of COVID-19 cases and deaths due to fine particulate matter exposure during the 2020 wildfires in the United States. Sci Adv 7(33):eabi8789. (Synopsis(https://factor.niehs.nih.gov/2021/10/papers/dert/#a4))

In-house research

Male hormones protect against gastric inflammation

Male hormones can protect from inflammation and pre-cancerous conditions in the stomach, according to a study by NIEHS scientists. The study offers novel mechanistic insight into how male hormones regulate stomach inflammation by restraining specialized immune cells.

The authors observed that glucocorticoids, a type of steroid hormone produced by adrenal glands, is required to protect female mice from stomach inflammation. However, in male mice, they found that in addition to glucocorticoids, male sex hormones provide an additional layer of protection against stomach inflammation. The researchers found that the inflammatory response from specific immune cells called type 2 innate-lymphoid cells (ILC2) drives the development of gastric inflammation. Importantly, the study showed that male sex hormones directly repress the proinflammatory state of ILC2, thereby preventing harmful inflammation.

Citation: Busada JT, Peterson KN, Khadka S, Xu X, Oakley RH, Cook DN, Cidlowski JA. 2021. Glucocorticoids and androgens protect from gastric metaplasia by suppressing group 2 innate lymphoid cell activation. Gastroenterology 161(2):637–652.e4. (Synopsis(https://factor.niehs.nih.gov/2021/7/papers/dir/#a3)) (Story)

Several types of lung dendritic cells involved in neutrophilic asthma

NIEHS scientists have identified five clusters of conventional dendritic cells (cDC2s) in the lungs of mice following their inhalation of house dust extract. As a result, the team is closer to understanding the cellular and molecular mechanisms involved in pulmonary diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), and asthma.

The researchers used mass cytometry, single cell RNA sequencing, and a mouse model of asthma to assess how the developmental progression of cDC2s affects their ability to promote differentiation of the distinct T-helper (Th) cell lineages, Th2 and Th17. The researchers found that Ly6C, a cell-surface marker of immature dendritic cells, is associated with those cells’ ability to promote the differentiation of Th17 cells. This finding is important because cDC2s in the lung direct immune responses to inhaled agents in the environmental bioaerosol.

Citation: Izumi G, Nakano H, Nakano K, Whitehead GS, Grimm SA, Fessler MB, Karmaus PW, Cook DN. 2021. CD11b+ lung dendritic cells at different stages of maturation induce Th17 or Th2 differentiation. Nat Commun 12(1):5029. (Synopsis(https://factor.niehs.nih.gov/2021/10/papers/dir/#a2))

Synaptic plasticity rescue in a mouse model of Rett syndrome

NIEHS researchers discovered that removal of perineuronal nets (PNNs) — a specialized form of extracellular matrix — in a Mecp2-null mouse model of Rett syndrome (RTT) salvages synaptic plasticity in the hippocampal area CA2 of the brain early in postnatal development. Synaptic plasticity refers to the brain’s ability to respond to environmental stimuli. RTT is a neurodevelopmental disorder characterized by normal development in the first year of life, followed by rapid, significant decline in cognitive, motor, and social function. The condition affects 1 in 10,000 girls worldwide.

The authors previously found that PNNs limit synaptic plasticity in CA2, a region associated with social learning in mice and an area that is atypically resistant to long-term potentiation. The scientists observed increased PNNs in the CA2 region of postmortem human tissue from an individual with RTT and found that PNNs develop precociously in the murine model of RTT.

Citation: Carstens KE, Lustberg DJ, Shaughnessy EK, McCann KE, Alexander GM, Dudek SM. 2021. Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome. J Clin Invest 131(16):e137221. (Synopsis(https://factor.niehs.nih.gov/2021/9/papers/dir/#a5))

Oxylipins linked to exposure of consumer product chemicals

NIEHS researchers and their collaborators found an association between exposure to consumer product chemicals and oxylipins during pregnancy. Oxylipins are lipids that play important roles in inflammation, tissue repair, and blood clotting.

The researchers looked at biomarkers of exposure to three classes of consumer product chemicals, including phenols, phthalates, and organophosphate esters (OPEs) in the urine of 90 mothers during multiple points of pregnancy. These biomarkers were simultaneously examined alongside a panel of oxylipins found in serum.

The scientists demonstrated that several oxylipins involved in inflammatory responses were higher in pregnant women with elevated concentrations of urinary phenol, phthalate, and OPE biomarkers. These associations varied by the class of consumer product chemical and the pathway by which oxylipin was produced. Taken together, this study provides insight into how exposure to environmental chemicals during pregnancy affects specific processes of inflammation.

Citation: Welch BM, Keil AP, Bommarito PA, van T' Erve TJ, Deterding LJ, Williams JG, Lih FB, Cantonwine DE, McElrath TF, Ferguson KK. 2021. Longitudinal exposure to consumer product chemicals and changes in plasma oxylipins in pregnant women. Environ Int 157:106787. (Synopsis(https://factor.niehs.nih.gov/2021/11/papers/dir/#a2))

Scientists link impaired mitochondrial autophagy with autoimmunity

Using a mouse model that lacked the gene IRGM1, a research team led by NIEHS researchers determined that a buildup of defective mitochondria led to an autoimmune condition that resembled Sjogren’s syndrome. In humans, Sjogren’s is characterized by dryness in the mouth, eyes, and other parts of the body. The research suggests a possible mechanism for how autoimmunity develops in people.

IRGM1 is the mouse version of a human gene called IRGM. These genes are responsible for autophagy, a process that removes malfunctioning organelles from the cell. In addition to displaying symptoms of autoimmunity, the scientists determined that IRGM1 knockout mice also had evidence for increased signaling by an inflammatory protein called type 1 interferon. The scientists also provided evidence that the DNA and RNA that spills out of faulty mitochondria elicit an immune response that causes an overproduction of type 1 interferon.

Citation: Rai P, Janardhan KS, Meacham J, Madenspacher JH, Lin WC, Karmaus PWF, Martinez J, Li QZ, Yan M, Zeng J, Grinstaff MW, Shirihai OS, Taylor GA, Fessler MB. 2021. IRGM1 links mitochondrial quality control to autoimmunity. Nat Immunol 22(3):312−321. (Synopsis(https://factor.niehs.nih.gov/2021/3/papers/dir/#a4)) (Story)

A molecular cascade shapes the fate of stem cells

NIEHS researchers have revealed how a protein called INO80 controls the fate of pluripotent stem cells, which can give rise to all cell types in the body.

INO80 is involved in many cellular and developmental processes, as well as neurological diseases and cancer. As a chromatin remodeler, INO80 can regulate gene activity by altering the structure of chromatin, which consists of DNA and proteins such as histones.

The researchers inactivated the INO80 gene in mouse stem cells at different developmental stages and found that INO80 enhanced the binding of a histone variant called H2A.Z to key DNA sequences at the later developmental stage. This event triggered the addition of certain chemical groups to histones, thereby decreasing the activity of nearby genes that play important roles in development. The findings revealed unexpected functions of INO80 in regulating the genomic positioning of H2A.Z and gene activity.

Citation: Yu H, Wang J, Lackford B, Bennett B, Li JL, Hu G. 2021. INO80 promotes H2A.Z occupancy to regulate cell fate transition in pluripotent stem cells. Nucleic Acids Res 49(12):6739–6755. (Synopsis(https://factor.niehs.nih.gov/2021/8/papers/dir/#a2))

Short sleep, apnea-specific hypoxia linked to kidney disease

Researchers at NIEHS led a team that reported that short sleep and apnea-specific hypoxia, which is the lack of adequate oxygen because of apnea, are associated with chronic kidney disease (CKD) in a multi-ethnic population. The findings indicate that sleep disturbance was twice as prevalent among African American participants with CKD compared with white participants. The research incorporated novel, more sensitive assessments of sleep apnea and evaluated these associations in a racially and ethnically diverse population. Such data are lacking in the literature.

The scientists found that very short sleep, five or fewer hours per night, and sleep apnea-specific hypoxia were associated with moderate-to-severe CKD. These sleep deficiencies may contribute to CKD by worsening known risk factors, such as dyslipidemia, hypertension, and type 2 diabetes. The association between sleep deficiencies and CKD could be studied by clinicians and public health professionals to address health disparities.

Citation: Jackson CL, Umesi C, Gaston SA, Azarbarzin A, Lunyera J, McGrath JA, Jackson WB, Diamantidis CJ, Boulware E, Lutsey PL, Redline S. 2020. Multiple, objectively measured sleep dimensions including hypoxic burden and chronic kidney disease: findings from the Multi-Ethnic Study of Atherosclerosis. Thorax 76(7):704–713. (Synopsis(https://factor.niehs.nih.gov/2021/2/papers/dir/#a3))

GLIS1 protein regulates pressure in eye, linked to human glaucoma risk

The gene regulatory protein GLIS1 is associated with glaucoma in humans and the regulation of intraocular pressure inside the eyes of mice, according to NIEHS researchers and their collaborators. This study sheds light on the cellular and molecular causes of the second most common cause of blindness in the U.S. and may lead to the development of new therapies.

In most cases, glaucoma is caused by an increase in intraocular pressure, which is largely regulated by an eye tissue known as the trabecular meshwork. The researchers found that mice lacking GLIS1 developed enlarged eyes and a long-lasting increase in intraocular pressure,

The study revealed that low levels of GLIS1 induce the degeneration of the trabecular meshwork, leading to inefficient drainage of the ocular fluid called the aqueous humor. The research also showed that GLIS1 regulates the expression of several glaucoma-associated genes in trabecular meshwork cells.

Citation: Nair KS, Srivastava C, Brown RV, Koli S, Choquet H, Kang HS, Kuo YM, Grimm SA, Sutherland C, Badea A, Johnson GA, Zhao Y, Yin J, Okamoto K, Clark G, Borras T, Zode G, Kizhatil K, Chakrabarti S, John SWM, Jorgenson E, Jetten AM. 2021. GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans. Nat Commun 12(1):4877. (Synopsis(https://factor.niehs.nih.gov/2021/10/papers/dir/#a3))

Histone crotonylation is crucial for early embryonic development

NIEHS researchers and their collaborators reported that an epigenetic modification known as histone crotonylation (Kcr) is necessary for the differentiation of human embryonic stem cells (hESCs) during early embryonic development. Epigenetics, the study of how genes are read and expressed, is known to be important in regulation of pluripotency and differentiation of hESCs in response to metabolic alterations, but the specific mechanisms were unclear.

Using immunofluorescence and quantitative proteomic analyses, the authors showed that histone Kcr, a specific epigenetic modification to the proteins that package DNA inside chromosomes, increases during a metabolic switch from glycolysis to oxidative phosphorylation early in the process by which hESCs differentiate into mesoendodermal cells. This increase induces mesoendodermal gene expression and promotes mesoendoderm differentiation in vitro and in vivo. The data directly link metabolic programming to histone Kcr and further demonstrate that Kcr plays a role in promoting mesoendodermal gene expression.

Citation: Fang Y, Xu X, Ding J, Yang L, Doan MT, Karmaus PWF, Snyder NW, Zhao Y, Li JL, Li X. 2021. Histone crotonylation promotes mesoendodermal commitment of human embryonic stem cells. Cell Stem Cell 28(4):748–763.e7. (Synopsis(https://factor.niehs.nih.gov/2021/3/papers/dir/#a5))

AEG12 inhibits mosquito-borne flavivirus by disrupting viral envelope

The mosquito protein AEG12 disrupts the lipid envelope that covers some viruses, according to NIEHS researchers and their collaborators. Flaviviruses — a class that includes dengue, yellow fever, and zika virus — are mainly transmitted by mosquitos and typically covered by a protective coating of lipids. Mosquitos produce AEG12 in response to a blood meal or flavivirus infection.

After solving the three-dimensional structure of AEG12 by X-ray crystallography, the researchers identified AEG12 as a lipid-binding protein. They further demonstrated that AEG12 was capable of rupturing membranes of red blood cells and inhibiting the replication of flaviviruses and other enveloped viruses, including human coronaviruses.

AEG12 breaks open the cells or virus by swapping the lipid it carries with those in the cell membrane or virus envelop. By doing so, AEG12 contributes to both insect digestion and the antiviral immune response.

Citation: Foo ACY, Thompson PM, Chen SH, Jadi R, Lupo B, DeRose EF, Arora S, Placentra VC, Premkumar L, Perera L, Pedersen LC, Martin N, Mueller GA. 2021. The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism. Proc Natl Acad Sci U S A 118(11):e2019251118. (Synopsis(https://factor.niehs.nih.gov/2021/5/papers/dir/#a2)) (Story)

Metformin may reduce risk of certain breast cancers

Although women with type 2 diabetes (T2D) may have increased breast cancer risk, use of the antidiabetic drug metformin may reduce that risk. A team led by NIEHS researchers found women with T2D and long-term metformin use were 38% less likely to develop estrogen receptor-positive (ER-positive) breast cancer compared with women without T2D. However, women with T2D and metformin use were at increased risk of ER-negative breast cancer and triple-negative breast cancer (TNBC).

The scientists used data from 44,541 women in the Sister Study, a prospective study of risk factors for breast cancer and other diseases. Participants were aged 35-74 years and breast-cancer free at enrollment. Although the researchers did not find an association between T2D and breast cancer overall, 74% of those with T2D used metformin, and long-term metformin treatment was associated with reduced risk of ER-positive breast cancer.

Citation: Park Y-MM, Bookwalter DB, O'Brien KM, Jackson CL, Weinberg CR, Sandler DP. 2021. A prospective study of type 2 diabetes, metformin use, and risk of breast cancer. Ann Oncol 32(3):351–359. (Synopsis(https://factor.niehs.nih.gov/2021/4/papers/dir/#a5))

Crystal structure of SARS-CoV-2 Nsp15 reveals new insights

NIEHS researchers and their colleagues used structural biology to study the endoribonuclease nonstructural protein 15 (Nsp15), an enzyme that cuts single- and double-strand viral RNA. Nsp15 is found in all coronaviruses and, through a complex process, helps the virus evade a host’s immune system. These findings may allow researchers to design therapeutics that bind to the Nsp15 active site of SARS-CoV-2, which could help treat COVID-19 cases.

Researchers used cryogenic electron microscopy, or cryo-EM, to visualize the structure of Nsp15. In addition to creating structural images, they performed molecular dynamics simulations to assess the biological function of the protein. They found that Nsp15 is stable and active when bound with RNA, but when it is not bound with RNA, Nsp15 constantly shifts and creates a wobble effect. Although the significance of the wobble is not completely understood, it may present a previously unexplored function.

Citation: Pillon MC, Frazier MN, Dillard LB, Williams JG, Kocaman S, Krahn JM, Perera L, Hayne CK, Gordon J, Stewart ZD, Sobhany M, Deterding LJ, Hsu AL, Dandey VP, Borgnia MJ, Stanley RE. 2021. Cryo-EM structures of the SARS-CoV-2 endoribonuclease Nsp15 reveal insight into nuclease specificity and dynamics. Nat Commun 12(1):636. (Synopsis(https://factor.niehs.nih.gov/2021/3/papers/dir/#a3))

When DNA repair goes awry

A molecule called polymerase (pol) mu may be a previously underappreciated and ironic source of mutations during DNA repair, according to NIEHS researchers and their collaborators.

Environmental and metabolic endogenous insults often trigger DNA damage, including double-strand breaks, which in turn may cause cancer or cell death. Double-strand breaks can be repaired with the aid of polymerases, which are proteins that synthesize DNA from building blocks called nucleotides. As with DNA, nucleotides are also damaged by environmental toxicants.

The researchers combined an imaging technique called time-lapse crystallography with computational simulations. The findings suggested that pol mu may cause mutations by incorporating a nucleotide called 8-oxo-rGTP into the genome during double-strand break repair.

Unfortunately, this process poses a persistent threat to genomic stability because it circumvents the intricate cellular defense network that typically protects against DNA damage.

Citation: Jamsen JA, Sassa A, Perera L, Shock DD, Beard WA, Wilson SH. 2021. Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair. Nat Commun 12(1):5055. (Synopsis(https://factor.niehs.nih.gov/2021/10/papers/dir/#a5))

Single-cell data shed light on genitalia formation

An NIEHS study could lead to a better understanding of diseases associated with defects in the external genitalia, potentially paving the way for more effective treatment strategies.

The researchers used single-cell messenger RNA sequencing in mouse embryos at critical developmental stages. Although the external genitalia in males and females were largely similar in cell composition and gene activity at the earliest stage, males and females showed genetic differences in key developmental pathways. These differences resulted in distinct cellular responses to the sex hormones androgen and estrogen, even though the cell populations were still highly similar in both sexes. By the last stage, differences in cell populations eventually arose, leading to sex-specific external genitalia. The findings suggest that the sex hormones help to synchronize various cell populations as they carry out unique roles in genitalia formation.

Citation: Amato CM, Yao HH. 2021. Developmental and sexual dimorphic atlas of the prenatal mouse external genitalia at the single-cell level. Proc Natl Acad Sci U S A 118(25):e2103856118. (Synopsis(https://factor.niehs.nih.gov/2021/8/papers/dir/#a5)) (Story)

Targeting signaling molecules in hosts could curb pneumonia

The ability of immune cells to eliminate pneumonia-causing bacteria is regulated by molecules called epoxyeicosatrienoic acids (EETs) and soluble epoxide hydrolase (sEH), the enzyme that degrades them, according to NIEHS researchers and their collaborators.

EETs are signaling molecules that have potent anti-inflammatory properties, but they are usually rapidly broken down in cells to less-active molecules by the sEH protein. The researchers used mice that were genetically engineered to have high EET levels due to disruption of the gene that codes for sEH. Macrophages in the lungs of these mice could not be activated to optimally engulf and destroy Streptococcus pneumoniae through a process called phagocytosis. However, pharmacological treatment with a compound that blocks EET receptors promoted the removal of this pneumonia-causing bacterium from the lungs. Additional experiments showed that EETs and sEH play similar roles in regulating phagocytosis by human macrophages.

Citation: Li H, Bradbury JA, Edin ML, Graves JP, Gruzdev A, Cheng J, Hoopes SL, DeGraff LM, Fessler MB, Garantziotis S, Schurman SH, Zeldin DC. 2021. sEH promotes macrophage phagocytosis and lung clearance of Streptococcus pneumoniae. J Clin Invest 131(22):e129679. (Synopsis(https://factor.niehs.nih.gov/2021/12/papers/dir/#a3)) (Story)

Division of the National Toxicology Program research

Environmental chemicals and cardiotoxicity

Researchers identified several pharmaceutical drugs and environmental chemicals that have cardiotoxic potential based on patterns of activity observed in in vitro assays.

Cardiovascular (CV) disease is the leading cause of death in the United States, but the contribution of environmental chemicals to CV disease is less well-studied. The scientists precisely defined six modes of CV failure and their molecular targets. Then, they harnessed data available from programs like Toxicology Testing in the 21st Century (Tox21) and the U.S. Environmental Protection Agency’s Toxicity Forecaster (ToxCast). By profiling the Tox21/ToxCast chemical library for cardiotoxicity and focusing on in vitro high-throughput screening assays, investigators identified several drugs and chemicals with bioactivity against the molecular targets of CV failure modes.

This analysis revealed environmental chemicals that were active at concentrations lower than those toxic to cells. The researchers used structural profiling to identify clusters of chemicals enriched for bioactivity.

Citation: Krishna S, Berridge B, Kleinstreuer N. 2020. High-throughput screening to identify chemical cardiotoxic potential. Chem Res Toxicol 34(2):566–583. (Synopsis(https://factor.niehs.nih.gov/2021/2/papers/dir/#a1))

NTP uses metabolomics to assess toxicity

Using benchmark concentration (BMC) analysis with human liver cells, the research team determined that different concentrations of compounds caused changes in detectable metabolites produced by liver cells. It is a new strategy that could estimate the safety of chemicals.

The researchers applied concentration-response modeling using BMC analysis to interpret mass spectrometry–based untargeted metabolomics data. Metabolomics is the large-scale detection and measurement of metabolites, or the molecules that are intermediates or end products after the body breaks down food, drugs, or chemicals.

The team exposed cultures of human liver cells to compounds that included relatively toxic drugs, such as the cancer drug tamoxifen and the antiretroviral medication ritonavir. Rising concentrations of drugs known to cause liver injury resulted in sharp increases in metabolic responses that were expected based on past research. By contrast, this effect did not occur for nontoxic compounds, such as sucrose and potassium chloride.

Citation: Crizer DM, Ramaiahgari SC, Ferguson SS, Rice JR, Dunlap PE, Sipes NS, Auerbach SS, Merrick BA, DeVito MJ. 2021. Benchmark concentrations for untargeted metabolomics vs. transcriptomics for liver injury compounds in in vitro liver models. Toxicol Sci 181(2):175−186. (Synopsis(https://factor.niehs.nih.gov/2021/5/papers/dir/#a1))

DNTP studies health effects of potentially toxic chemical from refineries

A study demonstrated differences across species in response to exposure to sulfolane, a potentially toxic compound used during industrial refining. Originally developed by Shell Oil Company in the 1950s, sulfolane has been detected in groundwater sources near refining sites. Currently, there are no federal regulatory limits for sulfolane levels in drinking water. Health effects of this chemical on humans have not been well-characterized, particularly after oral exposure.

The researchers compared the effects of sulfolane on rats, mice, and guinea pigs after 28 days of oral exposure to a wide range of doses. Male rats appeared to be the most sensitive to the compound, showing evidence of kidney abnormalities, whereas guinea pigs appeared to be the least sensitive. Sulfolane induced lesions in different tissues across the three species. Plasma levels were generally higher in rats and guinea pigs compared to mice, which corresponded to observed effects.

Citation: Shipkowski KA, Cora MC, Cesta MF, Robinson VG, Waidyanatha S, Witt KL, Vallant MK, Fallacara DM, Hejtmancik MR, Masten SA, Cooper SD, Fernando RA, Blystone CR. 2021. Comparison of sulfolane effects in Sprague Dawley rats, B6C3F1/N mice, and Hartley guinea pigs after 28 days of exposure via oral gavage. Toxicol Rep 8:581–591. (Synopsis(https://factor.niehs.nih.gov/2021/7/papers/dir/#a1))

NIEHS and partners harmonize environmental health language

Researchers from NIEHS and the international environmental health sciences community have proposed the creation of the Environmental Health Language Collaborative, an effort to develop and promote harmonized language in the field.

Through a community model, the collaborative seeks to standardize vocabulary, terminologies, and statistical and modeling approaches to enhance findability, shareability, and interoperability of data. The group supports increased use of artificial intelligence and machine learning to parse the enormous quantities of data and metadata produced through research.

The collaborative includes a community of practice as a hub of information and exchange of ideas, a forum for coordination and collaboration, and the development of a platform to address needs identified in use cases. The group will take advantage of communication structures in the Research Data Alliance model. NIEHS recently hosted a workshop to help advance this initiative.

Citation: Holmgren SD, Boyles RR, Cronk RD, Duncan CG, Kwok RK, Lunn RM, Osborn KC, Thessen AE, Schmitt CP. 2021. Catalyzing knowledge-driven discovery in environmental health sciences through a community-driven harmonized language. Int J Environ Res Public Health 18(17):8985. (Synopsis(https://factor.niehs.nih.gov/2021/10/papers/dir/#a1))

DNTP study shows how cobalt may cause cancer

Cobalt metal dust may cause lung cancer in rodents and humans by inducing oxidative stress in cells. Cobalt metal powder is used in the production of alloys, ceramics, batteries, and dyes, with numerous industrial applications.

Occupational inhalation exposure to cobalt alloys is known to cause lung cancer, but the health hazards due to pure cobalt metal are poorly understood. The researchers showed that exposure to cobalt metal ions triggers a process called oxidative stress, which is caused by the excessive buildup of free radicals, or reactive oxygen species, that damage DNA, proteins, and lipids.

DNA adducts due to oxidative stress were demonstrated in lung tissues from mice exposed to cobalt metal particles. Moreover, analysis of mouse lung tumors from this study revealed significant alterations in PI3K/AKT and MAPK signaling pathways that were previously implicated in human cancers.

Citation: Ton TT, Kovi RC, Peddada TN, Chhabria RM, Shockley KR, Flagler ND, Gerrish KE, Herbert RA, Behl M, Hoenerhoff MJ, Sills RC, Pandiri AR. 2021. Cobalt-induced oxidative stress contributes to alveolar/bronchiolar carcinogenesis in B6C3F1/N mice. Arch Toxicol 95(10):3171–3190. (Synopsis(https://factor.niehs.nih.gov/2021/11/papers/dir/#a1))