Papers of the Month
By Aidin Alejo Abdala, Mimi Huang, Victoria Placentra, Qing Xu, and Dahea You
NTP finds PFAS chain length affects elimination time in rats
Researchers from the Division of the National Toxicology Program (NTP) evaluated the toxicokinetics (TKs) of several poly- and perfluorinated alkyl substances (PFAS) in rats. PFAS are chemicals that are used in manufacturing nonstick properties in products and for other uses, such as fire-fighting foams. The study reported a correlation between PFAS chain length and TK properties, namely, that longer chain lengths displayed longer elimination times.
TK studies examine the rate at which a compound enters and leaves the body, while providing some information on the efficiency of its metabolic degradation. The chemical structures of most PFAS are stable, meaning the chemicals tend to persist in the environment and are not metabolically degraded, which increases human exposure. To address TK variability among PFAS, male and female rats were exposed by oral or intravenous administration to three carboxylate PFAS: perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), and perfluoerodecanoic acid (PFDA). The scientists measured concentrations in several tissues at different time points.
Although other researchers have conducted PFAS toxicity studies, TK studies are necessary to better understand the variability of exposure in the PFAS subclasses. This study provided a rigorous comparison of TK properties across a PFAS subclass. The data, along with existing toxicity studies, are necessary to extrapolate the animal results to humans, which may affect regulations of these chemicals. (VP)
Citation: Dzierlenga AL, Robinson VG, Waidyanatha S, DeVito MJ, Eifrid MA, Gibbs ST, Granville CA, Blystone CR. 2019. Toxicokinetics of perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) in male and female Hsd:Sprague dawley SD rats following intravenous or gavage administration. Xenobiotica; doi: 10.1080/00498254.2019.1683776 [Online 7 November 2019].
Mineralocorticoid receptors determine the cell fate of CA2 neurons
NIEHS researchers have found that mineralocorticoid receptors (MRs), a type of steroid receptor activated by corticosteroid hormones, control the gene profiles of neurons within the CA2 brain region, which is associated with learning and memory. The findings reveal essential roles of MRs in the development and maintenance of CA2 neurons, as well as CA2-related behaviors.
In response to environmental stress, the body secretes corticosteroids that bind to glucocorticoid receptors (GRs) or MRs and that induce changes of gene expression in the brain. GRs and MRs share the same glucocorticoid response element on the DNA promoters but differ in their brain locations and functions. MRs are highly enriched in the CA2 region of both mouse and human hippocampus. Because CA2 neurons display distinct features compared with neighboring neurons, the authors of this study investigated the biological influence of MRs on CA2 neurons.
Neuronal deletion of MRs at either embryonic, early postnatal development, or adulthood led to significantly reduced expression of CA2 molecular markers. Mice with CA2-targeted deletion of MRs also showed disrupted social behavior and altered responses to novel objects. Therefore, MRs control both the identity and function of CA2 neurons. (QX)
Citation: McCann KE, Lustberg DJ, Shaughnessy EK, Carstens KE, Farris S, Alexander GM, Radzicki D, Zhao M, Dudek SM. 2019. Novel role for mineralocorticoid receptors in control of a neuronal phenotype. Mol Psychiatry; doi: 10.1038/s41380-019-0598-7 [Online 7 November 2019].
RUNX1 important in maintaining fetal ovary identity
A study by NIEHS researchers and their international collaborators discovered that transcription factors RUNX1 and FOXL2 coordinate to support normal fetal ovary identity. RUNX1 is known to be well-conserved in multiple vertebrate species, playing a critical role in developmental processes of multiple organs.
Using their genetic mouse model, the scientists showed that RUNX1 interacts closely with FOXL2 at the genomic level to play a complementary role in supporting cell differentiation of the ovary. RUNX1 was much more highly expressed in mouse gonads that develop into ovaries compared with those that develop into the testis. The genetic loss of both RUNX1 and FOXL2, compared with the single loss of RUNX1 or FOXL2, led to more abnormal gene expression profiles and a notable masculinization in fetal ovaries. Further molecular investigations demonstrated that RUNX1 and FOXL2 bind to similar regions in the fetal ovarian genome and regulate a common set of genes to maintain the normal development of the fetal ovaries. .
Moreover, the study showed the conservation of this ovary-specific enrichment of RUNX1 during gonad development in other species, including humans. This work provides not only insights into the genomic control of sex determination in female gonads, but also potential candidate genes that are involved in human disorders of sex development. (DY)
Citation: Nicol B, Grimm SA, Chalmel F, Lecluze E, Pannetier M, Pailhoux E, Dupin-De-Beyssat E, Guiguen Y, Capel B, Yao HH. 2019. RUNX1 maintains the identity of the fetal ovary through an interplay with FOXL2. Nat Commun 10(1):5116.
Combined phthalate and stress exposure may lead to preterm birth
Phthalate exposure combined with high stress during pregnancy is associated with preterm birth, according to a team of researchers led by NIEHS scientists. Phthalates, compounds that are present in personal care products and plastics, have been commonly found in pregnant women. Although exposures to phthalates or stress have been independently associated with increased risk for preterm birth, their joint impact was unknown before this study.
Using data from 783 pregnant women participating in The Infant Development and the Environment Study (TIDES), researchers obtained questionnaire information about stressful events in each trimester and measured urinary phthalate metabolites from up to three trimesters. Team members found an increased risk of preterm birth associated with phthalate metabolites in urine during the third trimester, but not the first trimester. Furthermore, adding the variable of stress to third trimester data showed that the association between phthalate metabolites in urine and preterm birth risk was only significant for women who reported at least one stressful life event during pregnancy versus those who did not. This study paves the way for understanding how combined exposure to environmental and psychosocial factors affect pregnancy. (AAA)
Citation: Ferguson KK, Rosen EM, Barrett ES, Nguyen RHN, Bush N, McElrath TF, Swan SH, Sathyanarayana S. 2019. Joint impact of phthalate exposure and stressful life events in pregnancy on preterm birth. Environ Int 133(Pt B):105254.
TLR8 SNP and p53-dependent immune responses to respiratory virus
Researchers at the NIEHS have shown that a certain genetic polymorphism can modify the innate immune response to viral infections. This knowledge could be used to diagnose or predict patient response to viral infections.
The researchers found that a single nucleotide polymorphism (SNP) in the toll-like receptor 8 (TLR8) gene enables enhanced expression of TLR8 by the master regulator and tumor suppressor p53. TLR8 is a sensor that recognizes viral single-stranded RNA and activates the innate immune system. Upon p53 activation, human lymphocytes containing the p53-responsive SNP expressed higher levels of TLR8 than those without the SNP. This SNP-dependent regulation of TLR8 expression correlated with synergistic increases in the proinflammatory interleukin-6 cytokine following incubation with a TLR8 ligand.
Importantly, the authors established the clinical relevance of the p53 responsive SNP to immune responses, which supported their earlier views of a p53-immune axis in humans. They showed that the p53 SNP was associated with significantly higher severity of respiratory syncytial virus disease in a cohort of hospitalized infants. In addition to the important implications to many microbial infections influenced by TLR8, the findings may be relevant in cancer therapies. Because p53 is often mutated in cancer cells, p53 status could be relevant in immunotherapies that may have a TLR8 component. (MH)
Citation: Menendez D, Snipe J, Marzec J, Innes CL, Polack FP, Caballero MT, Schurman SH, Kleeberger SR, Resnick MA. 2019. p53-responsive TLR8 SNP enhances human innate response to respiratory syncytial virus. J Clin Invest 129(11):4875–4884.
(Aidin Alejo Abdala is an Intramural Research Training Award [IRTA] postbaccalaureate fellow in the NIEHS Clinical Investigation of Host Defense Group. Mimi Huang, Ph.D., is an IRTA fellow in the Systems Toxicology Group at NTP. Victoria Placentra is an IRTA postbaccalaureate fellow in the NIEHS Mutagenesis and DNA Repair Regulation Group. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group. Dahea You, Pharm.D., Ph.D., is an IRTA postdoctoral fellow in the NTP Biomolecular Screening Branch.)