Papers of the Month
By David Banks, Brandi Baughman, Robert Brown, Douglas Ganini da Silva, and Kelly Shipkowski
NTP evaluates toxicity of replacement flame retardants
National Toxicology Program (NTP) researchers and their collaborators found that replacement flame retardants may cause the same toxic effects previously seen with older brominated flame retardants. The scientists initiated the study because polybrominated diphenyl ether (PBDE) flame retardants are no longer used in commercial products due to human health concerns, and organophosphate flame retardants (OPFRs) have taken their place. However, experts raised the possibility that these replacement flame retardants — which have been detected in house dust, drinking water, and human tissues — may be toxic as well.
The research team used the roundworm Caenorhabditis elegans as an alternative toxicological model to evaluate the toxicity of the brominated flame retardants and their replacements. The work showed that 11 of the 12 flame retardants tested, including both organophosphate and brominated chemicals, were active in different toxicity endpoints tested in the C. elegans model. One OPFR, triphenyl phosphate, appeared to induce the same toxicity as some of the PBDEs, including similar effects on C. elegans reproduction and larval development. (KS)
Behl M, Rice JR, Smith MV, Co CA, Bridge M, Hsieh JH, Freedman JH, Boyd WA. 2016. Comparative toxicity of organophosphate flame retardants and polybrominated diphenyl ethers to Caenorhabditis elegans. Toxicol Sci; doi:10.1093/toxsci/kfw162 [Online 26 Aug 2016].
MicroRNA-33 regulates cross talk between cholesterol and inflammation
Researchers led by scientists at NIEHS revealed a novel pathway linking cholesterol metabolism and inflammation. They identified microRNA-33 as a promoter of cellular cholesterol accumulation, which indirectly enhances the inflammatory response of immune cells. Identification of novel pathways that affect inflammation is of great importance, because inflammation is the principal mechanism used by the immune system against infections and injury.
MicroRNA-33 is a short, noncoding RNA that decreases the levels of two proteins involved in the removal of cholesterol from cells, the ATP binding cassette transporters A1 and G1. By decreasing these transporters, microRNA-33 promotes cholesterol accumulation. One important function of cholesterol in cells is the formation of structures known as lipid rafts in the plasma membrane. Lipid rafts are used as signaling platforms for sensing inflammatory triggers, such as bacteria and viruses.
This research showed that cells of the immune system with increased levels of microRNA-33 displayed elevated lipid raft signals and, as a result, became more responsive to inflammatory stimuli. Interestingly, microRNA-33 and cholesterol levels declined after sustained exposure of immune cells to bacterial stimuli, which implied that microRNA-33 downregulation might also serve as a constraint in chronic inflammation and lipid overload conditions. (DGS)
Lai L, Azzam KM, Lin WC, Rai P, Lowe JM, Gabor KA, Madenspacher JH, Aloor JJ, Parks JS, Naar AM, Fessler MB. 2016. MicroRNA-33 regulates the innate immune response via ATP binding cassette transporter-mediated remodeling of membrane microdomains. J Biol Chem 291(37):19651−19660.
Mapping testis development from start to finish
Scientists at NIEHS time-mapped the differentiation of interstitial and supporting cells of the mouse fetal testis from sex determination to the fully-differentiated adult state. By following the lineage progression of emerging cell types from gonadal primordium to differentiated testis, researchers laid important groundwork for determining how cell identities emerge throughout development toward a functional organ.
By probing for distinct changes in protein expression at different time points throughout fetal development, researchers were able to chart events as to when new cell types emerged from their undifferentiated precursors. At the onset of sex determination of the gonads, the gonadal primordium of male and female embryos, which are indistinguishable during this time, begins to diverge into what will be their respective, adult reproductive organs — testis and ovary. At this point, for embryos with a Y chromosome, a distinct cell population, referred to as somatic progenitors that express the transcription factor Wilms’ tumor 1, or WT1, begin progression into cell types that consist of the interstitial and supporting cells of the testis. Scientists mapped the emergence of these cells as they acquired distinct expression patterns unique to each population. They identified HES1, SOX9, and GLI1 as effective markers for these transitions, and successfully mapped somatic cell differentiation in the testis by following those cells that acquired them. (DB)
Liu C, Rodriguez K, Yao HH. 2016. Mapping lineage progression of somatic progenitor cells in the mouse fetal testis. Development 143:3700–3710.
A novel glucocorticoid-mediated mechanism involved in heart health
Using in vivo and in vitro mouse models of cardiac injury, NIEHS researchers found that the transcription factor Klf13 is directly regulated by the glucocorticoid receptor (GR). Glucocorticoids are steroid hormones that suppress inflammation. This finding offers a novel role for glucocorticoids and Klf13 in heart cells, or cardiomyocytes, which may have clinical implications for the prevention of heart failure in humans induced by cardiovascular toxicity.
The scientists used cardiomyocyte-specific GR knockout mice, wild-type mice, murine primary adult cardiomyocytes, HL-mice cardiomyocytes, and H9C2 rat cardiomyocytes. They found that expression levels, or the amount of Klf13 protein produced, were induced by glucocorticoids. They also demonstrated that Klf13 regulated both pro-apoptotic and anti-apoptotic genes in mouse cardiomyocytes. Overexpressing Klf13 and glucocorticoid-induced Klf13 protected cardiomyocytes that were challenged with cytotoxic chemicals, such as doxorubicin. Together, these findings support a potential mechanism by which glucocorticoids decrease cardiomyocyte toxicity through the glucocorticoid-induced upregulation of KLF13.
Because many lifesaving chemotherapeutics, such as doxorubicin, have dose-limiting toxicities due to cardiac cell death, scientists can use this information to understand the mechanisms that influence this toxicity. (RB)
Cruz-Topete D, He B, Xu X, Cidlowski JA. 2016. Kruppel-like factor 13 is a major mediator of glucocorticoid receptor signaling in cardiomyocytes and protects these cells from DNA damage and death. J Biol Chem 291(37):19374−19386.
Advances in nanotechnology could lead to improved pulmonary safety
NIEHS researchers and collaborators have revealed a novel methodology for reducing the lung toxicity caused by multiwalled carbon nanotubes (MWCNTs), which are cylindrical carbon molecules used in a variety of applications, including structural engineering, optics, and biosensors. This report is the first to show that adding a natural sugar molecule, such as hyaluronic acid (HA), to MWCNTs reduces their potential for injuring lungs.
The safety profile of MWCNTs is still largely undefined, but previous research has suggested that MWCNT inhalation may result in inflammation, fibrosis, and granuloma formation in the lungs. Because high molecular weight HA is an anti-inflammatory polysaccharide found in all vertebrates, the researchers wanted to see if attaching HA to MWCNTs could mitigate their toxic effects. The scientists functionalized or attached HA to MWCNTs, and added the complexes to mice and human lung cell cultures. They monitored the cells for proinflammatory and profibrotic changes, and saw decreased injury.
Exposure to HA-functionalized MWCNTs resulted in significantly decreased lung fibrosis and mucous cell metaplasia, which are hallmarks of chronic airway disorders, and reduced inflammation in primary human cells, compared with nonfunctionalized MWCNTs. These findings provide insights into the beneficial impacts of HA functionalization on MWCNT toxicity and may pave the way for advances in pulmonary chemotherapy and occupational safety. (BB)
Hussain S, Ji Z, Taylor AJ, DeGraff LM, George M, Tucker CJ, Chang CH, Li R, Bonner JC, Garantziotis S. 2016. Multiwalled carbon nanotube functionalization with high molecular weight hyaluronan significantly reduces pulmonary injury. ACS Nano 10(8):7675−7688.