Environmental Factor – February 2023: Intramural Papers of the Month

Study shows how two concerning flame retardants may harm health

Chemicals called triphenyl phosphate (TPHP) and isopropylated phenyl phosphate (IPP) produce hazardous reproductive and developmental outcomes in rats, according to researchers from the NIEHS Division of Translational Toxicology (DTT).

Organophosphate esters (OPE) compounds, which include TPHP and IPP, have increasingly been used as flame retardants and plasticizers in consumer products and building materials during the past two decades. This trend is worrying because OPE exposure can begin early in life, and the long-term effects remain unknown. In particular, TPHP and IPP used as flame retardants have raised concerns of increased hand-to-mouth exposure in children. Yet the potential risk from exposure to either TPHP or IPP during fetal development has been unclear.

To answer this question, the researchers analyzed toxicity data for TPHP and IPP in rats. Reproductive performance was altered by exposure to any level of IPP, and relatively high concentrations of TPHP. Developmental toxicity effects included a decrease in the number of pups, live pups, and pup survival throughout lactation. (DTT is conducting longer-term, more in-depth assessments to determine whether these preliminary findings are replicated.)

In offspring, exposure to both compounds produced toxic outcomes at relatively high levels and reduced body weight and delayed puberty at lower concentrations. Taken together, the findings pave the way for future studies examining the potential impact of these flame retardants on human health.

CitationWitchey SK, Sutherland V, Collins B, Roberts G, Shockley KR, Vallant M, Krause J, Cunny H, Waidyanatha S, Mylchreest E, Sparrow B, Moyer R, Behl M. 2022. Reproductive and developmental toxicity following exposure to organophosphate ester flame retardants and plasticizers, triphenyl phosphate and isopropylated phenyl phosphate, in Sprague Dawley rats. Toxicol Sci kfac135.

Gene implicated in Alzheimer’s disease regulated by a molecule called AANCR

A new study has revealed how the sequences and structures of RNAs regulate transcription and disease susceptibility, according to NIEHS researchers and their collaborators.

RNA is modified by hundreds of chemical reactions and folds into innumerable shapes. However, the regulatory role of RNA sequence and structure and how dysregulation leads to diseases remain largely unknown.

To address this knowledge gap, the researchers focused on RNA abasic sites, which do not contain purine or pyrimidine bases, located on three-stranded nucleic acid structures called R-loops. The results revealed how RNA abasic sites in R-loops regulate the transcription of DNA into RNA by pausing a multiprotein complex called RNA polymerase II. In addition, the researchers discovered that a molecule called APOE-activating noncoding RNA (AANCR) regulates the transcription and expression of apolipoprotein E (APOE) — a gene implicated in Alzheimer’s disease.

Moreover, the findings showed that DNA sequence variants in AANCR are associated with APOE expression and Alzheimer’s disease. Together, the data highlight the importance of the folding and modification of RNA in cellular regulation and demonstrate that dysregulation underlies common complex diseases. Future studies can assess how variation in AANCR and APOE interact to affect Alzheimer’s disease, potentially paving the way for novel RNA-based therapeutics.

CitationWatts JA, Grunseich C, Rodriguez Y, Liu Y, Li D, Burdick JT, Bruzel A, Crouch RJ, Mahley RW, Wilson SH, Cheung VG. 2022. A common transcriptional mechanism involving R-loop and RNA abasic site regulates an enhancer RNA of APOE. Nucleic Acids Res 50(21):12497–12514.

Exploring the link between early-life trauma and diabetes

The association between traumatic childhood experiences and type 2 diabetes varies by race and ethnicity, according to NIEHS researchers and their collaborators.

Childhood trauma has been linked to an increased risk of metabolic syndrome and type 2 diabetes in adulthood. But prior studies that examined this relationship have yielded mixed results. They also have not investigated traumatic childhood experiences beyond abuse and neglect while considering potential racial and ethnic differences.

To address this knowledge gap, the researchers analyzed survey data from a diverse sample of 42,173 middle- to older-aged women. Black/African American and Latina participants had a higher burden of early-life trauma, metabolic syndrome, and type 2 diabetes compared with non-Hispanic White counterparts. Reporting any traumatic childhood experience, including a natural disaster or major illness, was associated with a 13% higher risk of type 2 diabetes for the entire group. This link was strongest among Latinas and was partially explained by metabolic syndrome.

According to the authors, the study suggests that Latina women may be an understudied population at a particularly high risk of type 2 diabetes associated with early-life trauma. In addition, tailored prevention and intervention efforts that protect youth from trauma and inhibit likely mediators such as metabolic abnormalities may help ease the burden of type 2 diabetes among women. Also, according to the authors, climate change will increase children’s risk of experiencing disasters, so traumatic childhood experiences and environmental vulnerability data should be considered when developing disaster preparedness and response programs.

CitationGaston SA, Riley NM, Parks CG, Woo JMP, Sandler DP, Jackson CL. 2022. Racial/ethnic differences in associations between traumatic childhood experiences and both metabolic syndrome prevalence and type 2 diabetes mellitus risk among a cohort of US women. Diabetes Care dc221486.

Revealing the risks of residing near concentrated animal feeding operations

Autoimmunity is associated with living in proximity to a concentrated animal feeding operation (CAFO), according to NIEHS researchers and their collaborators.

CAFOs, which typically house thousands of animals, are a source of environmental pollution and have been linked to various health problems. Yet the relationship between immune-mediated diseases and residing in proximity to a CAFO has been unclear.

To address this knowledge gap, the researchers explored associations between immune-mediated diseases and living less than eight miles from a CAFO using data from the NIEHS Personalized Environment and Genes Study. They assessed a group of 6,464 participants residing in North Carolina, where the swine industry is an important source of revenue and commerce. The results suggest that there is an increased risk of autoimmune diseases and rheumatoid arthritis in individuals living close to swine CAFOs.

They also analyzed genetic variants called single nucleotide polymorphisms (SNPs) in a subset of 1,541 participants. In particular, the findings reveal a potential role of the prototypical xenobiotic response genes aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT) in conferring risk. This is the first report of the association of rheumatoid arthritis with the ARNT SNPs rs11204735 and rs1889740.

Taken together, the results contribute to the growing body of evidence indicating that it is essential to manage emissions from CAFOs and minimize their public health and environmental impacts. According to the authors, the study could pave the way for novel genetically-targeted or other preventive approaches for certain immune-mediated diseases.

CitationAyala-Ramirez M, MacNell N, McNamee LE, McGrath JA, Akhtari FS, Curry MD, Dunnon AK, Fessler MB, Garantziotis S, Parks CG, Fargo DC, Schmitt CP, Motsinger-Reif AA, Hall JE, Miller FW, Schurman SH. 2022. Association of distance to swine concentrated animal feeding operations with immune-mediated diseases: An exploratory gene-environment study. Environ Int 171:107687.

Ensuring the accuracy of DNA replication across species

Proteins called Rrm3 and PIF1 have unanticipated functions in promoting the fidelity of DNA replication, according to NIEHS researchers and their collaborators.

The duplication of genomes is a challenging undertaking, and a variety of mechanisms help to reduce errors during this process. For example, proteins called DNA helicases play critical roles in DNA replication and repair across species. The budding yeast genome encodes two Pif1 family DNA helicases called Rrm3 and Pif1, which promote replication and suppress DNA damage. In humans, mutations in human PIF1 (hPIF1) are found in some high-risk breast cancer families, suggesting that it may also suppress tumors.

The researchers discovered novel functions of both yeast Rrm3 and hPIF1 in preventing mutations during DNA replication. The results showed that Pif1 serves as a backup for Rrm3 in suppressing mutations in yeast. In addition, human PIF1’s role in mutation avoidance provides a possible novel explanation for its potential function as a tumor suppressor.

Taken together, the results suggest that the role of Pif1 family helicases in mutation avoidance may be evolutionarily conserved. According to the authors, the question now is how many additional, as yet unknown, factors are involved in replication fidelity and tumor suppression.

CitationZhou ZX, Follonier C, Lujan SA, Burkholder AB, Zakian VA, Kunkel TA. 2022. Pif1 family helicases promote mutation avoidance during DNA replication. Nucleic Acids Res gkac1127.

(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)

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