Papers of the Month
By Yu-Wei Chen, Anika Dzierlenga, Katie Glenn, Kiri Hoff, and Qing Xu
NTP evaluates the fetal transfer of vinpocetine
The dietary supplement vinpocetine and its metabolite apovincaminic acid (AVA) were detected in pregnant rats and their fetuses in a toxicokinetic study following repeated oral exposure, according to National Toxicology Program (NTP) scientists. Vinpocetine is widely used for its ability to purportedly enhance cognitive function, including use by women of child-bearing potential. This study is the first to demonstrate the transfer of vinpocetine and AVA to the rat fetus, and suggests potential human fetal exposure to these compounds.
The NTP performs constant assessments in rats and rabbits to address some of the knowledge gaps in vinpocetine toxicity, including the potential for fetal toxicity due to exposure to vinpocetine during pregnancy. This evaluation will help to put any toxicity findings into a larger context by correlating internal exposure to vinpocetine with the toxicity observed. Overall, the comparison of rat toxicokinetic data from the current investigation with that observed in humans suggests that findings from the NTP toxicity studies may be relevant to humans. (AD)
Citation: Waidyanatha S, Toy H, South N, Gibbs S, Mutlu E, Burback, B, McIntyre BS, Catlin N. 2017. Systemic exposure of vinpocetine in pregnant Sprague Dawley rats following repeated oral exposure: an investigation of fetal transfer. Toxicol Appl Pharmacol 338:83¬–92.
GLIS3 is essential for biosynthesis of thyroid hormones
NIEHS researchers have revealed that transcriptional factor GLI-similar 3 (GLIS3) is required for biosynthesis of thyroid hormones (THs) and proliferation of thyroid follicular cells that generate THs. The findings offer new insight into the development and treatment of thyroid disorders, including hypothyroidism and goiter, which is an enlarged thyroid.
THs are crucial for embryonic development, growth, and control of the body’s metabolism. Thyroid-stimulating hormones (TSHs) from the pituitary gland control TH production by interacting with the TSH receptor (TSHR) to regulate genes involved in TH synthesis and thyroid development. Recent studies have associated mutations of the GLIS3 gene with congenital hypothyroidism, meaning newborns cannot make enough THs at birth. In this study, scientists investigated the function of GLIS3 in the thyroid and identified its critical role in TH biosynthesis.
Using a mouse model with a GLIS3 deficiency, they found that loss of GLIS3 caused a major reduction in TH levels and proliferation of follicular cells, and prevented goiter development. GLIS3 directly bound to the promoters of several genes responsible for TH biosynthesis. GLIS3 knockout mice exhibited suppressed expression of these genes and impaired activation of the TSH-mediated mTORC1 pathway that promotes cell proliferation. The data indicate that GLIS3 acts downstream of TSH/TSHR and is a key regulator of TH biosynthesis. (QX)
Citation: Kang HS, Kumar D, Liao G, Lichti-Kaiser K, Gerrish K, Liao XH, Refetoff S, Jothi R, Jetten AM. 2017. GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation. J Clin Invest 127:4326–4337.
Certain lung inflammation sustained by TLR4 signaling
Recent findings from NIEHS researchers suggest that Toll-like receptor 4 (TLR4), a protein that induces innate immune responses, may be a therapeutic target for some chronic lung diseases, including those that are resistant to conventional glucocorticoid treatment.
Chronic pulmonary conditions, such as asthma or interstitial lung diseases, are characterized by T helper (Th) 17 cells and related neutrophilic inflammation. To investigate how Th17 cells are sustained in chronically inflamed lung tissue, scientists exposed mice to inhalation of allergen alone, or allergen with environmental agents, such as extracts of common house dust. They found that long-term exposure to environmental agents maintained lung inflammation. These agents also led to weight loss and lung pathophysiology that were reminiscent of interstitial lung diseases. In contrast, when allergens were present, but environmental signals were discontinued, the Th17-dependent inflammation gradually diminished.
The researchers also found that the effect of environmental agents is mediated by TLR4 signaling in multiple cell types, primarily in lung hematopoietic cells and antigen-presenting cells that express the protein CD11c. Overall, these results improve our understanding of Th17-dependent inflammation, and suggest that Th17-dependent lung diseases may be treated by blocking the TLR4 signaling pathway. (YWC)
Citation: Shalaby KH, Lyons-Cohen MR, Whitehead GS, Thomas SY, Prinz I, Nakano H, Cook DN. 2017. Pathogenic Th17 inflammation is sustained in the lungs by conventional dendritic cells and TLR4 signaling. J Allergy Clin Immunol; doi: 10.1016/j.jaci.2017.10.023 [Online 14 November 2017].
Potential novel therapeutic target for metabolic diseases and cancer
Removing the two diphosphoinositol pentakisphosphate kinase genes (PPIP5Ks) from HCT116 colonic epithelial cells causes hypermetabolism and slow growth, according to NIEHS scientists and their collaborators. The PPIP5K knockout cells display a hypermetabolic state in which the cells consume greater amounts of glucose, coupled with enhanced mitochondrial respiration and elevated cellular adenosine triphosphate levels. The finding suggests that PPIP5Ks may be target genes for the treatment of diabetes and obesity. PPIP5K knockout cells also have elevated levels of the cell-cycle regulator, p53, which is associated with a slower growth rate. Thus, PPIP5Ks are a potential therapeutic target for colon cancer.
The authors found that PPIP5K knockout cells exhibited complete loss of the signaling molecule bis-diphosphoinositol tetrakisphosphate (InsP8), the enzymatic product of PPIP5Ks, and threefold elevated levels of the substrate diphosphoinositol pentakisphosphate (InsP7). To determine the role of each signaling molecule, PPIP5K knockout cells were exposed to N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl) purine (TNP), which inhibits the inositol hexakisphosphate kinases (IP6Ks). This inhibition returned the amount of InsP7 to wildtype levels without rescuing InsP8 levels. This novel pharmacological strategy provides a tool for separating the roles of InsP8 and InsP7. Overall, the study provides new insight into the significance of PPIP5Ks for regulating cellular growth and metabolism. (KH)
Citation: Gu C, Nguyen HN, Ganini D, Chen Z, Jessen HJ, Gu Z, Wang H, Shears SB. 2017. KO of 5-InsP7 kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype. Proc Natl Acad Sci U S A 114(45):11968–11973.
Oil spill dispersants associated with adverse health effects
Researchers at NIEHS, along with their collaborators, found that potential exposure to dispersants used during the 2010 Deepwater Horizon oil spill response was associated with respiratory, dermal, and eye irritation. The study is the first to directly evaluate associations between dispersants and both acute and longer term effects, up to 3 years later, on human health.
The Gulf Long Term Follow-Up Study (GuLF STUDY) tracks the health of workers involved in the 2010 Deepwater Horizon oil spill cleanup. Large quantities of two different dispersants, Corexit EC9527A and Corexit EC9500A, were used to facilitate the breakup of the resulting oil slick. The researchers used GuLF STUDY enrollment interview data to determine associations between possible dispersant exposure and reported adverse health effects.
The researchers used self-reported data on clean-up tasks, work timing, and location to classify whether workers were potentially exposed to dispersants. The scientists found the strongest associations between dispersant exposure and having symptoms, such as burning in the nose, throat, or lungs, tightness in the chest, and burning eyes while working on the clean-up. Although the associations between dispersants and symptoms at the time of enrollment 1 to 3 years later were weaker, some associations remained significant. The researchers demonstrated that these associations were not due to simultaneous exposure to the oil itself, but could not rule out that other oil-spill related chemicals, such as cleaning agents, played a role. (KG)
Citation: McGowan CJ, Kwok RK, Engel LS, Stenzel MR, Stewart PA, Sandler DP. 2017. Respiratory, dermal, and eye irritation symptoms associated with Corexit EC9527A/EC9500A following the Deepwater Horizon oil spill: findings from the GuLF STUDY. Environ Health Perspect 125(9):097015. (Story)
(Yu-Wei Chen, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Developmental Neurobiology Group. Anika Dzierlenga, Ph.D., is an IRTA fellow in the NIEHS Developmental and Reproductive Toxicology Group. Katie Glenn, Ph.D., is a fellow in the NIEHS Mechanisms of Mutation Group. Kiri Hoff, Ph.D., is an IRTA fellow in the NIEHS Mitochondrial DNA Replication Group. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)