Papers of the Month
By Janelle Weaver and Amanda Riccio
How a convulsive compound affects brain development
Maternal seizures induced by high levels of exposure to the chemical called 4-Methylimidazole (4-MeI) may alter the formation of early neuronal networks in offspring, according to researchers from the Division of Translational Toxicology.
Clinically, the impact of maternal seizures during pregnancy has been a long-term concern because they represent a risk to the fetus and have been linked to adverse effects on offspring. This concern has been supported by experimental animal models of targeted pharmaceutical-induced seizures; however, how this translates to non-pharmacological compounds remains unclear.
Building upon the existing experimental literature on the impact of maternal seizures on offspring, the researchers employed a rat model of maternal seizures induced by high-dose levels of the compound, 4-MeI. This chemical compound is used in manufacturing and is an undesirable low-level byproduct in some heated foods and beverages, such as coffee.
In the offspring, the researchers discovered evidence that 4-MeI exposure sufficient to induce maternal seizures resulted in a pattern of gene expression that was different than those reported for drug-induced seizures. The pattern was suggestive of a disruption or delay in critical processes associated with neurons and their connections, potentially affecting the development of early neuronal networks.
According to the authors, the study demonstrates the importance of considering the in-utero environment and maternal health status when evaluating gestational effects of exposure on brain development. (JW)
Citation: Massri AJ, Fitzpatrick M, Cunny H, Li JL, Harry GJ. 2023. Differential gene expression profiling implicates altered network development in rat postnatal day 4 cortex following 4-Methylimidazole (4-MeI) induced maternal seizures. Neurotoxicol Teratol 100:107301.
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.
Interferon gamma (IFN-γ) is a protein that enhances host defense by targeting antimicrobial genes, including immunity-related GTPases (IRGs). Animals deficient in Irgm1, the best studied IRG, succumb to numerous bacterial and protozoal infections, similar to animals lacking IFN-γ. A few years ago, NIEHS researchers reported that Irgm1-deficient mice spontaneously produced excess levels of a signaling molecule called type I interferon (IFN-I). Although IFN-I is protective against viruses, it may compromise antibacterial host defense.
Consistent with this idea, the researchers have now discovered that IFN-I drives the susceptibility of Irgm1-deficient mice to bacteria. Specifically, mice lacking Irgm1 succumbed to Mycobacterium tuberculosis and Listeria monocytogenes, but Irgm1-deficient mice lacking the IFN-I receptor were resistant. Additional results suggest that Irgm1 supports host defense by preventing excess IFN-I from compromising the function of blood cells called myeloid cells.
Taken together, the findings challenge the long-prevailing paradigm regarding how Irgm1 supports host defense. In particular, the results reveal an important role of IFN-I in this process, separate from the previously reported cell-intrinsic mechanism involving IFN-γ. According to the authors, more research is needed to further investigate the molecular mechanisms underlying IFN-I-mediated susceptibility against bacterial infection. (JW)
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 e171982.
Historical exposure to fine particulate matter is linked to breast cancer
Long-term historical exposure to airborne particles less than 2.5 micrometers in diameter (PM2.5) is associated with a higher incidence of breast cancer, according to NIEHS researchers and their collaborators.
Breast cancer is the most commonly diagnosed malignancy among women worldwide. Despite active research on the role of air pollution in breast cancer, there has been inconsistent evidence for an association with PM2.5. Most previous studies have assessed breast cancer risk in relation to PM2.5 exposure at or around the time of study enrollment, with few considering more historic exposures when PM2.5 levels were higher.
To fill this knowledge gap, the researchers evaluated the link between historic concentrations of PM2.5 and incident breast cancer in a large, geographically spread U.S. cohort. The sample included 196, 905 female participants enrolled from 1995-1996 who did not have a prior history of cancer and were followed through 2017. The researchers estimated a five-year average PM2.5 concentrations at their baseline residence between 1980 and 1984.
Living in areas with greater than the average levels of PM2.5 was associated with an 8% higher incidence of breast cancer overall. This association was particularly evident for women with estrogen receptor–positive tumors, which may be more likely to be influenced by endocrine-disrupting compounds compared with other tumor subtypes. Future work should consider region-specific patterns and the potential contribution of PM2.5 chemical constituency in modifying the observed association with breast cancer. (JW)
Citation: White AJ, Fisher JA, Sweeney MR, Freedman ND, Kaufman JD, Silverman DT, Jones RR. 2023. Ambient fine particulate matter and breast cancer incidence in a large prospective US cohort. J Natl Cancer Inst djad170.
Gestational exposure to flame retardant chemicals may be widespread
Among pregnant people, frequent detection of biological markers, or biomarkers, of exposure to flame retardants and plasticizers suggests widespread exposure, with higher exposure linked to sociodemographic factors, according to NIEHS researchers and their collaborators.
The use of organophosphate esters (OPEs) — a class of chemicals often added to consumer products either to improve their fire resistance or to increase plasticity — has increased since the 2000s. OPE exposure is associated with neurotoxicity, developmental and reproductive toxicity, and endocrine disruption. Although pregnant people and their developing fetuses may be more susceptible to OPE effects, detailed analysis of trends in OPE exposure during pregnancy are limited.
To address this gap, NIEHS researchers assessed biomarkers of OPE exposure in urine across three time points in pregnant people participating in the LIFECODES Fetal Growth Study from 2007 to 2018. They found that five biomarkers of OPE exposure were detected in 60% or more of the study participants.
In addition, the researchers analyzed whether sociodemographic factors, such as participant age, education, self-reported race and ethnicity, and pregnancy factors, such as pre-pregnancy body mass index, parity, or the season of study visit could be used as predictors of OPE exposure. They found higher burdens of exposure among participants with higher pre-pregnancy body mass index, those belonging to racial and ethnic minority populations, younger participants, and those with lower educational attainment.
To date, this study is among the largest with detailed information on trends and predictors of OPE biomarkers among pregnant people. According to the authors, the results highlight the need for continued study of OPE exposures to better understand the potential health risks associated with exposure. (AR)
Citation: Bommarito PA, Friedman A, Welch BM, Cantonwine M, Ospina M, Calafat AM, Meeker JD, McElrath TF, Ferguson KK. 2023. Temporal trends and predictors of gestational exposure to organophosphate ester flame retardants and plasticizers. Environ Int 180:108194.
Immune-protecting protein could curb colon cancer
An enzyme called DNASE1L3 may promote antitumor immunity and suppress tumors of various types, including colon cancer, according to NIEHS researchers and their collaborators.
Deficiency of DNASE1L3 leads to the development of autoimmune diseases in both humans and mice, yet little is known about the role of this protein in the regulation of antitumor immunity.
To address this knowledge gap, the researchers systematically investigated the possible role of DNASE1L3 in mediating the interaction between immune cells and cancer cells in both humans and mice. In humans, the results revealed decreased levels of DNASE1L3 in tumor infiltering dendritic cells, and this was associated with poor patient prognosis for many cancer types.
In mice, deficiency of this protein delayed tissue recovery after damage, increased chronic inflammation and immune cell dysfunction, impaired antitumor immunity, and enhanced tumor formation and growth in several colon cancer models.
According to the authors, the study unveils a previously unknown link between DNASE1L3 and antitumor immunity, and further suggests that restoration of DNASE1L3 activity may represent a potential therapeutic approach for anticancer therapy. Moreover, the bioinformatic analysis of cancer patients indicates that DNASE1L3 could be evaluated as a predictive biomarker for risk and prognosis of various human cancers. (JW)
Citation: Li W, Nakano H, Fan W, Li Y, Sil P, Nakano K, Zhao F, Karmaus PW, Grimm SA, Shi M, Xu X, Mizuta R, Kitamura D, Wan Y, Fessler MB, Cook DN, Shats I, Li X, Li L. 2023. DNASE1L3 enhances antitumor immunity and suppresses tumor progression in colon cancer. JCI Insight 8(17):e168161.