Papers of the Month
By Megan Avakian
Promising new diagnostic tool for Parkinson’s disease
NIEHS grantees developed an accurate and noninvasive assay to diagnose Parkinson’s disease, a neurodegenerative condition that is misdiagnosed more than 20% of the time. The new assay is an improvement over current Parkinson’s disease diagnostic tests that are often inaccurate, invasive, or can only be conducted after death. The study authors state that if validated in larger cohort studies, the assay could facilitate earlier Parkinson’s disease diagnosis and treatment.
A key marker of Parkinson’s disease is the misfolding and clumping of the protein alpha-synuclein (alpha-syn) in the brain and other tissues. The researchers previously developed an assay to detect misfolded alpha-syn levels in postmortem brain and cerebrospinal fluid. Here, they extended and optimized the assay to assess skin samples from confirmed Parkinson’s disease cases and controls. Researchers analyzed frozen skin samples from 25 cases and 25 controls, and skin samples preserved in formaldehyde from 12 cases and 12 controls.
Skin samples from Parkinson’s disease cases had significantly higher levels of misfolded alpha-syn compared to controls. Among frozen skin samples, the assay correctly identified case and control samples 96% of the time. Among formaldehyde-preserved skin samples, the assay identified cases and controls with 75% and 83% accuracy, respectively.
According to the authors, study results clearly demonstrate that levels of misfolded alpha-syn in skin can serve as a diagnostic marker for Parkinson’s disease, providing a critical tool for initiating early intervention.
Citation: Manne S, Kondru N, Jin H, Serrano GE, Anantharam V, Kanthasamy A, Adler CH, Beach TG, Kanthasamy AG. 2020. Blinded RT-QuIC analysis of alpha-synuclein biomarker in skin tissue from Parkinson's disease patients. Mov Disord; doi: 10.1002/mds.28242 [Online 22 Sep 2020].
Predicting cancer-causing potential of PAH chemicals
NIEHS-funded scientists have developed a method to better predict the cancer-causing potential of polycyclic aromatic hydrocarbons (PAHs), a class of more than 1,500 chemicals that result from combustion of organic matter and fossil fuels. PAH exposures occur as complex environmental mixtures, making it difficult to tease apart the cancer-causing potential of individual chemicals in the mixture.
The researchers exposed a 3D model of human lung tissue to individual PAHs and identified genes with altered expression following exposure. Using computational approaches, they grouped the genes into gene sets related to specific biological pathways. They then looked for gene sets that were consistent across PAH chemicals with similar cancer-causing potential.
More than 9,500 genes were differentially expressed in PAH-exposed tissue compared to controls. The researchers identified four genes sets that, when combined, best predicted PAH carcinogenicity. These gene sets were related to pathways involved in cell differentiation processes, blood vessel formation, cell cycle regulation, and aryl hydrocarbon receptor signaling, which is important in the body’s response to environmental pollutants. Notably, the gene sets that were most affected by exposure to the PAH chemical benzo[a]pyrene (BAP) did not overlap with the four gene sets that best classified PAH carcinogenicity. This result challenges current risk assessment methods, which assume the mechanisms by which BAP causes cancer are representative of other carcinogenic PAHs.
According to the authors, results support the use of pathway-based gene sets and 3D human tissue models to better predict the cancer-causing potential of PAHs.
Citation: Chang Y, Huynh CTT, Bastin KM, Rivera BN, Siddens LK, Tilton SC. 2020. Classifying polycyclic aromatic hydrocarbons by carcinogenic potency using in vitro biosignatures. Toxicol In Vitro 69:104991.
Prenatal lead exposure alters gut microbiome
Lead exposure in the womb alters the infant gut microbiome, according to NIEHS-funded researchers. Both lead exposure and the early life microbiome have been linked to similar developmental health outcomes, but it has been unclear whether lead-related health effects are partially driven by the gut microbial community. This is the first human study to examine the influence of prenatal lead levels on the gut microbiome.
The researchers mapped growth rings in naturally shed teeth from 146 children to assess lead levels present in teeth before and after birth. Using genetic sequencing methods, they determined the types and abundance of bacteria and fungi present in child stool samples collected at approximately one and six months of age.
Prenatal tooth lead levels were significantly associated with the gut fungal community at one month of age. Specifically, higher lead resulted in a lower number of fungal species shown to be sensitive to lead and a higher number of lead-resistant fungal species. Lead did not have a significant effect on the newborn gut bacterial community. Differences in the microbial community were found for prenatal, but not postnatal, lead levels. This result highlights the advantage of using baby teeth to capture multiple exposure time points both before and after birth.
According to the researchers, the link between lead exposure and the infant gut microbiome could play a role in the impact of lead on childhood development.
Citation: Sitarik AR, Arora M, Austin C, Bielak LF, Eggers S, Johnson CC, Lynch SV, Kyun Park S, Hank Wu KH, Yong GJM, Cassidy-Bushrow AE. 2020. Fetal and early postnatal lead exposure measured in teeth associates with infant gut microbiota. Environ Int 144:106062.
PFAS profiles in seabirds point to a shift in chemical production
Seabird tissue samples contain high levels of both legacy and emerging per- and polyfluoroalkyl substances (PFAS), according to NIEHS-funded researchers. Study results reflect the shift toward production of new PFAS to replace legacy chemicals. PFAS are a large group of manmade chemicals. Due to their environmental persistence and known impacts on human health, many legacy PFAS have been phased-out of production.
The researchers used seabirds as indicators of environmental PFAS contamination. They measured 36 PFAS in the livers of 31 juvenile seabirds found dead off the coasts of Massachusetts, Rhode Island, and North Carolina. They also assessed bird phospholipid liver content, which plays a key role in metabolism and reproduction.
Nearly all birds had high levels of perfluorooctanesulfonic acid (PFOS) despite phase-out of the chemical in the early 2000s. The researchers identified, for the first time, three novel PFAS compounds manufactured in recent years to replace legacy PFAS. These novel PFAS were mainly found in birds near a PFAS production site. However, they were also present in birds with no connection to that site, suggesting the novel chemicals can travel long distances in the environment. Birds with higher PFOS had lower liver phospholipid content, a previously unreported finding.
Study results confirm the persistence of legacy PFAS the environment and reflect a shift in the types of PFAS in production. According to the authors, understanding PFAS levels in the environment ultimately stands to benefit public health, as humans rely on the same air, water, and land systems that sustain wildlife.
Citation: Robuck AR, Cantwell MG, McCord JP, Addison LM, Pfohl M, Strynar MJ, McKinney R, Katz DR, Wiley DN, Lohmann R. 2020. Legacy and novel per- and polyfluoroalkyl substances in juvenile seabirds from the U.S. Atlantic Coast. Environ Sci Technol 54(20):12938-12948.
(Megan Avakian is a science writer for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)