Papers of the Month
By Sara Amolegbe
Genetic basis for algal bloom toxicity
NIEHS grantees identified a cluster of genes involved in the production of domoic acid, a toxin produced by certain harmful algal blooms. Domoic acid can sicken marine mammals and accumulate in seafood, posing a potential threat to human health.
The researchers studied the marine phytoplankton Pseudo-nitzschia, a type of algae that has been found in major harmful algal bloom events. They examined patterns of biological activity in Pseudo-nitzschia grown in water with limited phosphate and increased carbon dioxide. These growth conditions are known to contribute to domoic acid production. The team analyzed genome-wide changes in RNA expression and identified a cluster of genes that are switched on when the phytoplankton produces domoic acid.
Harmful algal blooms are difficult to predict, and bloom-causing organisms typically possess complex, large genomes. According to the authors, knowledge of how the genes for domoic acid production are turned on could improve monitoring of algal blooms and may be used to identify conditions that trigger toxin production.
Citation: Brunson JK, McKinnie SMK, Chekan JR, McCrow JP, Miles ZD, Bertrand EM, Bielinski VA, Luhavaya H, Obornik M, Smith GJ, Hutchins DA, Allen AE, Moore BS. 2018. Biosynthesis of the neurotoxin domoic acid in a bloom-forming diatom. Science 361(6409):1356–1358.
Respiratory support source of phthalates in NICUs
A new study funded by NIEHS identified noninvasive respiratory support equipment — specifically, nasal prongs that deliver oxygen and air pressure — as a source of phthalate exposure in the neonatal intensive care unit (NICU). Although multiple studies have demonstrated elevated phthalate markers in NICU patients, specific sources of phthalate exposure were not previously identified.
Premature infants were studied during NICU hospitalization. Researchers recorded daily exposure to specific NICU medical equipment in 71 infants. They analyzed 149 urine specimens for phthalate metabolites. The team reported that phthalate markers in urine were 95-132 percent higher for infants exposed to certain medical equipment compared with those without equipment exposure. Phthalate mixtures relevant to neurobehavioral development were significantly associated with noninvasive respiratory support. Feeding supplies and intravenous lines were not significantly associated with these phthalate mixtures.
According to the authors, their discovery of the source of potentially neuroactive phthalate exposure provides an avenue to reduce phthalate exposure among NICU patients. The study also suggested that exposure to common and clinically relevant phthalates still exists, despite previous efforts by hospital NICUs and medical equipment manufacturers to limit exposure by changing the materials used in feeding supplies.
Citation: Stroustrup A, Bragg JB, Busgang SA, Andra SS, Curtin P, Spear EA, Just AC, Arora M, Gennings C. 2018. Sources of clinically significant neonatal intensive care unit phthalate exposure. J Expo Sci Environ Epidemiol; doi: 10.1038/s41370-018-0069-2. [Online 21 Sept 2018].
Caspase-2 enzyme implicated in fatty liver disease
NIEHS grantees discovered that a protein-cleaving enzyme known as caspase-2 is a major driver of nonalcoholic steatohepatitis (NASH), which is the most aggressive form of nonalcoholic fatty liver disease (NAFLD). They reported that caspase-2 controls the buildup of cholesterol and triglycerides in liver tissue by activating sterol regulatory element binding proteins, the master regulators of fatty tissue formation in the liver.
Researchers used mice susceptible to liver-specific endoplasmic reticulum stress, a factor that accelerates the progression of benign NAFLD, and fed them a high-fat diet to elicit NASH-like disease. Using this model, the scientists measured changes to enzymes during NASH progression and found that the onset of NASH correlated with increased expression of caspase-2.
When they knocked out the caspase-2 gene in the mice, the team observed reductions in all aspects of NASH, including lipid droplet accumulation as well as liver damage, inflammation, and scarring. The researchers also observed decreased NASH progression when they treated the mice with a specific caspase-2 inhibitor.
Examination of human liver specimens from patients with benign NAFLD or aggressive NASH, confirmed that caspase-2 expression was also elevated in humans with NASH. According to the authors, an inhibitor of this enzyme may potentially provide an effective way to stop the progression that leads to NASH, and possibly even reverse early symptoms.
Citation: Kim JY, Garcia-Carbonell R, Yamachika S, Zhao P, Dhar D, Loomba R, Kaufman RJ, Saltiel AR, Karin M. 2018. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P. Cell 175(1):133–145.e15.
Generational impacts of arsenic on DNA methylation
Arsenic exposure across generations was associated with common DNA methylation changes despite different exposure timing, according to an NIEHS-funded study. The new analysis also suggested that some of the DNA methylation changes altered by arsenic exposure might have the potential to be inherited.
The study was based in Hetao Plain, Inner Mongolia, China, where deep wells containing high levels of arsenic in water sources were switched to reduce arsenic exposure in the early 1990s. Researchers compared households exposed to arsenic before the wells were switched with unexposed households. The study included three generations — grandparents, parents, and grandchildren — living in the same household. The grandparents were exposed to arsenic in adulthood, and the parents were exposed in the womb or early in life.
The researchers isolated DNA from blood and examined DNA methylation patterns across the genome. They identified a number of DNA methylation differences between exposed and unexposed people and showed that arsenic exposure might leave detectable DNA methylation changes, even when exposure occurred decades earlier. Members of exposed families shared common genome regions where DNA was differentially methylated, despite different exposure timing. Because the changes were also seen in the grandchildren, the researchers suggested that these methylation patterns might be inherited.
According to the authors, the common DNA methylation regions associated with an increased risk for disease development might be able to serve as biomarkers for identifying individuals at risk for arsenic-induced skin lesions and cancers, regardless of when arsenic exposure occurred.
Citation: Guo X, Chen X, Wang J, Liu Z, Gaile D, Wu H, Yu G, Mao G, Yang Z, Di Z, Guo X, Cao L, Chang P, Kang B, Chen J, Gao W, Ren X. 2018. Multi-generational impacts of arsenic exposure on genome-wide DNA methylation and the implications for arsenic-induced skin lesions. Environ Int 119:250–263.