Papers of the Month
By Kelley Christensen and Janelle Weaver
Emerging contaminant GenX is not a safe alternative
Prenatal exposure to hexafluoropropylene oxide-dimer acid, or GenX, causes sex-specific metabolic and liver problems in adult mice, according to NIEHS researchers and their collaborators.
GenX is the modern-day replacement for perfluorooctanoic acid (PFOA) in many industrial applications and consumer products, but it is also a widespread environmental pollutant, and its health effects are unclear. PFOA is a global, persistent environmental contaminant associated with adverse metabolic outcomes.
To address this knowledge gap, the researchers exposed pregnant mice to daily oral doses of GenX or PFOA. Prenatal exposure to the chemicals induced harmful metabolic outcomes in adult mice, but the effects depended on dose, diet, and sex. GenX-exposed males fed a normal diet displayed increased weight gain and fat mass, fatty liver, and sensitivity to the hormone insulin. By contrast, females that were exposed to GenX or PFOA and fed a high-fat diet showed an increase in liver cell death.
Taken together, the findings show that exposure to relatively low doses of GenX in the womb may lead to metabolic disease in adult males and liver damage in females. According to the authors, the results suggest that GenX may not be a safe alternative to PFOA. (JW)
Citation: Cope HA, Blake BE, Love C, McCord J, Elmore SA, Harvey JB, Chappell VA, Fenton SE. 2021. Latent, sex-specific metabolic health effects in CD-1 mouse offspring exposed to PFOA or HFPO-DA (GenX) during gestation. Emerg Contam 7:219–235.
How memory-boosting receptors affect different brain cells
Activation of alpha7 nicotinic acetylcholine receptors (nAChRs) has distinct effects on the responses of different types of neurons in a brain region called the hippocampus, according to NIEHS researchers and their collaborators.
Stimulation of alpha7 nAChRs enhances learning and memory and promotes the maturation of adult-born neurons. Moreover, treatments targeting these receptors improve cognitive deficits associated with Alzheimer’s disease, schizophrenia, and Down’s syndrome. However, the cellular mechanisms underlying these effects remain elusive. Specifically, it has not been clear whether alpha7 nAChRs mobilize different signaling pathways in distinct neuronal populations.
To address this question, the researchers studied how stimulation of alpha7 nAChRs affects the responses of granule cells and GABAergic neurons in the hippocampus, which plays a critical role in learning and memory. In brain slices, alpha7 nAChR activation increased levels of the signaling molecules Ca2+ and cAMP in granule cells but not in GABAergic neurons. Similarly, recordings in mice revealed that nicotine injection increased alpha7 receptor-dependent activity of granule cells but did not increase the firing rate of GABAergic neurons.
Taken together, the results shed new light on the action of alpha7 nAChR on brain circuitry. According to the authors, the study paves the way for effective treatments that improve cognitive function in patients with a broad range of brain disorders. (JW)
Citation: Cheng Q, Lamb P, Stevanovic K, Bernstein BJ, Fry SA, Cushman JD, Yakel JL. 2021. Differential signalling induced by alpha7 nicotinic acetylcholine receptors in hippocampal dentate gyrus in vitro and in vivo. J Physiol 599(20):4687–4704.
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. Although EETs and sEH mediate many inflammatory responses, their roles in lung bacterial infection have not been clear. In particular, little is known how these molecules affect the functions of macrophages — cells that help orchestrate immune responses to pathogens.
To address this question, 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.
According to the authors, drugs that block EET receptors may offer a new treatment strategy that targets the host rather than the pathogen to combat bacterial pneumonia. (JW)
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. (Story)
Small for gestational age a limited tool to measure infant mortality risk
An NIEHS-led international team has determined that small for gestational age (SGA) — a widely used method to identify at-risk infants — is scarcely better than a coin toss in predicting infant outcomes. The team also looked at gestational age at delivery as a potentially more effective predictor of neonatal mortality.
The scientists analyzed 3.8 million U.S. births and 300,000 Norwegian births using receiver operating characteristic curves to evaluate the cut point at which birthweight percentiles most successfully identify infants at risk. An area under the curve of 100% represents perfect discernment between two possible outcomes (in this case, neonatal death or survival), whereas 50% is no better than flipping a coin. There was no definition of SGA that performed substantially better than a coin toss. The team also assessed the ability of SGA to predict cerebral palsy, another outcome strongly related to birthweight. SGA was even less useful for identifying infants at risk. In contrast, preterm birth (as expected) was strongly predictive.
These results call into question the practical utility of SGA, a measure widely used in clinical and public health research. (KC)
Citation: Wilcox AJ, Cortese M, McConnaughey DR, Moster D, Basso O. 2021. The limits of small-for-gestational-age as a high-risk category. Eur J Epidemiol 36(10):985–991.
Epigenome-wide study of DNA methylation following pesticide exposure
An international research team led by NIEHS scientists conducted an epigenome-wide analysis of DNA methylation in relation to nine active pesticide ingredients in current use, as well as seven that have been banned. DNA methylation is a cellular mechanism to control gene expression and occurs when a methyl group attaches to DNA.
The researchers analyzed blood samples collected as part of the Agricultural Lung Health Study using Illumina’s EPIC array. For each of the sixteen pesticide ingredients, the team used statistical methods to compare DNA methylation among farmers who used a specific pesticide with those who had never used it.
Among the study’s 1,170 male farmers of European ancestry living in Iowa and North Carolina, the researchers found 162 differentially methylated C-phosphate-G sites (CpGs) across nine pesticide ingredients. None of the 162 differentially methylated CpGs overlapped across the ingredients, indicating pesticide-specific methylation. DNA methylation is critical for gene expression; alterations could contribute to the biological mechanisms that underpin the long-term health effects of chronic pesticide exposure. (KC)
Citation: Hoang TT, Qi C, Paul KC, Lee M, White JD, Richards M, Auerbach SS, Long S, Shrestha S, Wang T, Beane Freeman LE, Hofmann JN, Parks C; BIOS Consortium, Xu CJ, Ritz B, Koppelman GH, London SJ. 2021. Epigenome-wide DNA methylation and pesticide use in the Agricultural Lung Health Study. Environ Health Perspect 129(9):97008.
(Kelley Christensen is a contract writer and editor for the NIEHS Office of Communications and Public Liaison [OCPL]. Janelle Weaver, Ph.D., is a contract writer for OCPL.)