Papers of the Month
Extramural
By Megan Avakian
Modified RNA segments may induce neurological disease, inform treatment
NIEHS-funded researchers uncovered a mechanism through which nucleotide repeat expansions contribute to neurological diseases. Nucleotide repeats are short segments of DNA or RNA, usually one to six or more nucleotides in length, that repeat multiple times in a row within a gene. Too many nucleotide repeats, called a nucleotide repeat expansion, can alter how the gene or its resulting protein function. Studies suggest that the CAG repeat expansion — named for its repeating cytosine, adenine, and guanine nucleotides — may contribute to development of multiple neurodegenerative disorders.
The researchers conducted rodent, roundworm, and fruit fly studies to investigate the relationship between CAG repeat expansions and neurological diseases. They found that a protein referred to as TRMT61A attached a methyl group to a nucleotide within the CAG repeat RNA, creating a new molecule called N1-methyladenosine (m1A).
In each animal study, levels of m1A increased as the number of CAG repeats increased. In roundworms, a longer CAG repeat sequence resulted in deterioration of the neuron network; this effect was alleviated by expression of the protein ALKBH3, which can remove the damaging methyl group. Fruit flies with ALKBH3 had lower levels of m1A in repeated CAG segments and longer lifespans than those without the protein.
Another protein called TDP-43 bound strongly to m1A in CAG repeat RNA. This binding altered TDP-43’s location within the cell and caused it to clump together, forming protein clusters. Both protein clustering and relocation are hallmarks of neurological disease.
The results offer insight into how nucleotide repeat expansions contribute to neurological diseases and reveal a novel pathological function of m1A. The authors noted these findings may inform therapeutic interventions for neurodegenerative diseases resulting from CAG repeat expansion.
Citation: Sun Y, Dai H, Dai X, Yin J, Cui Y, Liu X, Gonzalez G, Yuan J, Tang F, Wang N, Perlegos AE, Bonini NM, Yang XW, Gu W, Wang Y. 2023. m1A in CAG repeat RNA binds to TDP-43 and induces neurodegeneration. Nature 623(7987):580–587.
Disease-causing bacteria detected in coastal waters following Hurricane Ian
Several disease-causing Vibrio bacteria were present in waters along Florida’s Gulf coast following Hurricane Ian in 2022, NIEHS-funded researchers found. Their study approach could be used to predict when Vibrio infection risk is high, enabling decision-makers to better protect public health.
Vibrio bacteria naturally occur in the ocean. Some strains, including Vibrio parahaemolyticus and Vibrio vulnificus, cause an illness called vibriosis, which results in severe intestinal and skin infections and sometimes death. People contract vibriosis by eating raw or undercooked seafood or getting seawater in an open wound. Because Vibrio thrive in warm salt water, hurricanes and floods can increase exposure risk.
One month after Hurricane Ian, the researchers collected water and oyster samples from three sites in Lee County, an area significantly affected by the hurricane. Next, they used genomic analyses to identify disease-causing microbial species and genes in the samples.
Water and oyster samples revealed 21 Vibrio species, including Vibrio parahaemolyticus and Vibrio vulnificus. In addition, the water samples contained genes that could render microbes more harmful to humans, including genes that confer antibiotic resistance, increase disease severity, and enable microbial transfer of genetic material to other organisms. Using environmental data from satellites, the researchers also found that increases in rainfall, storm surge, sea surface temperature, and chlorophyll concentration during and after Hurricane Ian favored Vibrio growth.
According to the authors, genetic analysis coupled with data from satellites provided a valuable approach to determining how changing environmental conditions affected the growth of harmful bacteria. They also noted the method could help inform development of early-warning systems to protect public health during hurricanes and floods.
Citation: Brumfield KD, Usmani M, Santiago S, Singh K, Gangwar M, Hasan NA, Netherland M Jr, Deliz K, Angelini C, Beatty NL, Huq A, Jutla AS, Colwell RR. 2023. Genomic diversity of Vibrio spp. and metagenomic analysis of pathogens in Florida Gulf coastal waters following Hurricane Ian. mBio e0147623.
Long-term air pollution exposure linked to postpartum depression
Mothers experiencing long-term exposure to air pollution during and after childbirth have an increased risk of postpartum depression (PPD), according to NIEHS-funded research. The study is one of the first to examine the relationship between air pollution and this major depressive disorder.
PPD affects approximately 10-20% of women worldwide. Mothers with PPD can experience intense feelings of sadness, hopelessness, and anxiety and are more likely to die from suicide. Infants born to mothers with PPD have an increased risk of developing cognitive, emotional, behavioral, and psychological problems.
The study included data from about 340,600 women with an average age of 30 years who gave birth in Southern California between 2008 and 2016. The researchers used the mothers’ home addresses, data from air pollution monitoring stations, and a publicly available air pollution data set to estimate monthly average maternal exposure. Specifically, they assessed exposure to the following air pollutants: ozone, nitrogen oxides, particulate matter (PM10), and fine particulate matter (PM2.5), which includes a mixture of chemicals, such as black carbon and organic matter. They used PPD evaluations conducted during postpartum medical visits and follow-up clinical interviews to assess maternal mental health.
Overall, mothers with an increased risk of PPD had higher exposure to ozone, PM10, and PM2.5 before and after childbirth. Among PM2.5 components, organic matter and black carbon were most associated with PPD risk. Certain demographic groups, including mothers aged 25-34 years and African American or Hispanic women, were more vulnerable to increased PPD risk from air pollution exposure.
Results suggest that developing interventions to reduce air pollution exposure may help alleviate the PPD disease burden, according to the authors.
Citation: Sun Y, Headon KS, Jiao A, Slezak JM, Avila CC, Chiu VY, Sacks DA, Molitor J, Benmarhnia T, Chen JC, Getahun D, Wu J. 2023. Association of antepartum and postpartum air pollution exposure with postpartum depression in Southern California. JAMA Netw Open 6(10):e2338315.
Fish as a model for chemical exposures and disease in Arctic Indigenous peoples
NIEHS-funded researchers found that exposure to persistent organic pollutants (POPs) altered development and gene expression in a species of Arctic fish. Results suggest that the species can serve as a model for POP exposure and disease in human Arctic populations, including Indigenous communities.
POPs, which include polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and PFAS, are a group of chemicals that have been linked to a range of adverse health effects, including some cancers. Air and water currents carry POPs to the Arctic, where they accumulate in the food web and environment. Many Arctic Indigenous peoples subsist on fish and marine mammals, resulting in chronic POP exposure.
In response to concerns from Indigenous residents of Sivuqaq, Alaska, the researchers studied health risks posed by POP exposure. The team collected fish called ninespine stickleback from Troutman Lake in Sivuqaq during the summers of 2015 and 2018. They measured levels of POPs in the fish and assessed changes to commonly affected tissues, such as the liver.
Fish had the highest levels of PBDEs, followed by PCBs and PFAS. The fish also showed suppressed gonad development, abnormal livers, and altered expression of metabolism-related genes compared to fish collected elsewhere.
Because ninespine stickleback displayed similar contaminant profiles to Sivuqaq residents as well as POP-related outcomes relevant to human health, the species could be a suitable model organism to investigate community environmental health concerns, the authors stated.
Citation: Jordan-Ward R, von Hippel FA, Wilson CA, Rodriguez Maldonado Z, Dillon D, Contreras E, Gardell A, Minicozzi MR, Titus T, Ungwiluk B, Miller P, Carpenter D, Postlethwait JH, Byrne S, Buck CL. 2024. Differential gene expression and developmental pathologies associated with persistent organic pollutants in sentinel fish in Troutman Lake, Sivuqaq, Alaska. Environ Pollut 340(Pt 2):122765.
(Megan Avakian is a science writer for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)
