NTP finds that arsenic encourages stem cells to become cancer-like

Working with arsenic and prostate cancer cells, researchers in the National Toxicology Program Laboratory found that cancer cells can trick stem cells into becoming cancer-like using extracellular vesicles, which are structures surrounded by membranes that are released by cells. The team isolated a type of extracellular vesicle called an exosome from cells previously transformed by arsenic exposure. These exosomes changed normal prostate stem cells to look and act like cancer stem cells. When the exosomes were removed, no transformation happened. Arsenic is a known human carcinogen that targets the prostate.

Cells inside tumors have long been known to communicate with each other using secreted vesicles containing oncogenic factors, such as proteins and RNA, to recruit surrounding cells. The researchers demonstrated that the extracellular vesicles secreted by arsenic-transformed cells contained significantly higher amounts of mRNA for a host of oncogenes, genes that resist cell death, and inflammation-related genes. In addition, they found arsenic exposure changed the overall number of microRNAs loaded into exosomes. Further investigation of the oncogene KRAS concluded that exosomal KRAS plays a role in recruiting normal stem cells to function in the tumor environment following arsenic exposure. However, the scientists stress that more work remains to identify other factors involved in the transformation process. (GK)

Citation: Ngalame NNO, Luz AL, Makia N, Tokar EJ. 2018. Arsenic alters exosome quantity and cargo to mediate stem cell recruitment into a cancer stem cell-like phenotype. Toxicol Sci 165(1):40–49.

NRF2 mutation activates cancer target genes

NIEHS researchers and collaborators have identified a group of cancer-associated genes that are activated in tumors by the redox-responsive transcription factor NRF2. The findings shed new light on the mechanisms for NRF2 activation and the role of NRF2 in oncogenesis.

As a master regulator of cellular responses to free radicals, NRF2 binds with DNA sequences known as antioxidant response elements (AREs) and controls the expression of an array of genes that protect cells from oxidative damage. However, in tumors from various organ systems, hyperactivity of NRF2 due to mutations of either NRF2 or its inhibitors has been found to promote cancer development. Researchers in this study hypothesized that hyperactivated NRF2 would provide growth advantages to cancer cells by dysregulating its target genes in tumors.

Using an integrative genomic approach, the researchers revealed a set of 32 NRF2 direct target genes that are commonly upregulated in tumors with hyperactivated NRF2, independent of cancer types. Compared with noncancer target genes, these cancer target genes possess AREs that bind more strongly with NRF2 and locate in regions where DNA is more accessible by regulatory proteins. In addition, high expression of NRF2 cancer target genes may infer hyperactivity of NRF2. Both conditions are associated with poor cancer survival. (QX)

Citation: Levings DC, Wang X, Kohlhase D, Bell DA, Slattery M. 2018. A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations. Redox Biol 19:235–249.

Male mice grow ovaries after single gene tweak

NIEHS scientists have shown that activating a gene called FOXL2 in the gonads of male mice can cause their testes to turn into ovaries. FOXL2, one of a handful of genes involved in sex determination, is maintained in a wide variety of organisms, including oysters, goats, mice, and humans. The finding suggests that sexual development is not set in stone, as once believed, but can shift in response to different genetic or environmental factors.

In their study, the researchers used a sophisticated technique called ChiP-seq to pinpoint the regions of the genome that are acted upon by FOXL2, a transcription factor that turns multiple genes on and off. The researchers then genetically engineered male mice to produce FOXL2 in their gonads and showed that their testes were transformed into ovaries, although not completely. Finally, they mapped out possible downstream targets of FOXL2 that could be responsible for its feminizing action.

The research indicates that a number of other factors — genetic and otherwise — are involved in ovarian development and sex determination. It opens the door to future studies that could yield important insights into sexual development disorders, which affect as many as one in 5500 humans. (MB)

Citation: Nicol B, Grimm SA, Gruzdev A, Scott G, Ray MK, Yao HH. 2018. Genome-wide identification of FOXL2 binding and characterization of FOXL2 feminizing action in the fetal gonads. Hum Mol Genet; doi: 10.1093/hmg/ddy312 [Online 13 September 2018]. (Story)

The brain’s stress chemical has surprising effects

A subset of brain cells that release a fight-or-flight signaling chemical called norepinephrine unexpectedly reduces anxiety in mice, according to a study by NIEHS researchers. The findings could explain why antidepressants that globally affect what are termed noradrenergic neurons have inconsistent effects, informing the search for drugs with more specific activity.

Norepinephrine has long been regarded as a stress chemical that triggers anxiety. However, according to the new study, noradrenergic neurons that transiently express a gene called Hoxb1 early in development have an opposite action, mimicking the effect of antidepressants by promoting a better coping response to stress and decreasing anxiety-like behavior.

To induce stress, the researchers forced mice to swim and recorded the time spent floating immobile to measure behavioral despair. To assess anxiety, the researchers recorded how much time mice spent in a comfortable, dark compartment of a box versus an aversive, illuminated section.

Genetically modified mice with hyperactive Hoxb1-noradrenergic neurons spent less time immobile than did normal mice in the swim test. Moreover, activation of Hoxb1-noradrenergic neurons increased the time mice spent in the illuminated portion of a box. These observations contrast with the general belief that norepinephrine signaling promotes the stress response and demonstrate that the noradrenergic system consists of multiple subpopulations with distinct functions. (JW)

Citation: Chen YW, Das M, Oyarzabal EA, Cheng Q, Plummer NW, Smith KG, Jones GK, Malawsky D, Yakel JL, Shih YI, Jensen P. 2018. Genetic identification of a population of noradrenergic neurons implicated in attenuation of stress-related responses. Mol Psychiatry; doi: 10.1038/s41380-018-0245-8 [Online 13 September 2018]. (Story)

School lunch linked to higher chemical levels in children’s urine

Eating school lunches is linked to higher levels of certain chemicals in children’s urine, according to a study published by NIEHS. Researchers contend this study may indicate that school lunch consumption is an important source of phthalate exposure in this age group.

Cafeteria food is often mass-prepared and packaged using plastic materials containing phthalates, which are potential endocrine disruptors. In analysis of data from the National Health and Nutrition Examination Survey (NHANES), researchers examined concentrations of phthalate metabolites in spot urine samples from students and assessed school lunch consumption using a questionnaire in which students or their proxies reported how many times per week students ate a complete school lunch. They also calculated associations between caloric intake from cafeteria food and phthalate metabolites in urine based on 24-hour dietary data.

The study found that children ages 6-11 years who regularly ate school lunches had higher levels of phthalates in their urine than children who never ate school lunches. Six of the seven phthalate metabolites measured were higher in children ages 6-11 years than in adolescents. Five of these contaminants were higher in all age groups that always ate school lunches compared with those who either sometimes or never ate school lunches. However, phthalate metabolites were not associated with caloric intake from cafeteria food. Further research is needed to confirm whether eating mass-packaged school lunches is the actual cause of higher levels of phthalates in urine. (FW)

Citation: Munoz I, Colacino JA, Lewis RC, Arthur AE, Meeker JD, Ferguson KK. 2018. Associations between school lunch consumption and urinary phthalate metabolite concentrations in U.S. children and adolescents: results from NHANES 2003-2014. Environ Int 121(Pt1):287–295.