Papers of the Month
By Cody Nichols, Alicia Richards, Kelly Shipkowski, Payel Sil, and Heather Vellers
NTP identifies endocrine-disrupting chemicals in Tox21 screen
National Toxicology Program (NTP) researchers collaborated with scientists across the country to screen approximately 10,000 chemicals for whether they activated estrogen-related receptor alpha (ERR-alpha), a nuclear receptor involved in numerous biological processes. The work used high-throughput techniques to search the Tox21 database and is the first comprehensive analysis of potential endocrine disruptors that affect ERR-alpha signaling. Endocrine disruptors are compounds that mimic the body’s hormones and interfere with normal hormonal communication and signaling throughout the body.
ERR-alpha is expressed at high levels in metabolically active tissues and plays a role in maintaining energy homeostasis in response to environmental cues. In certain types of breast and prostate cancers, increased expression of ERR-alpha can lead to worsened outcomes. Therefore, the scientists wanted to understand which chemicals might affect ERR-alpha activity, thereby impacting health and disease.
The scientists used genetically modified human embryonic kidney cell lines to evaluate which chemicals activated ERR-alpha. They found more than five clusters of agonists, which are molecules that initiate a biochemical response. One of the chemical clusters was structurally similar to statins, a group of pharmaceutical compounds that remove fat from the bloodstream. The authors say that additional studies will be necessary to determine the full effects of statins on ERR-alpha activity. (KS)
Citation: Lynch C, Zhao J, Huang R, Kanaya N, Bernal L, Hsieh JH, Auerbach SS, Witt KL, Merrick BA, Chen S, Teng CT, Xia M. 2018. Identification of estrogen-related receptor alpha agonists in the Tox21 compound library. Endocrinology 159(2):744−753.
Pesticide exposure increases risk of age-related macular degeneration
Scientists from NIEHS and other institutions linked pesticide exposure to age-related macular degeneration (AMD), a condition characterized by deterioration of the central portion of the retina. AMD is a leading cause of blindness in developed countries.
The research team studied medical records of participants in the Agricultural Health Study, which is an examination of pesticide applicators, mostly farmers, and their spouses in Iowa and North Carolina. Taking into account exposure to specific pesticides, the scientists compared individuals with AMD with those without symptoms to analyze exposure and disease risk.
The authors identified both general classes and specific pesticides that are associated with AMD. Classes associated with increased risks were organochlorine and organophosphate insecticides, and phenoxyacetate herbicides. Specific pesticides associated with AMD included chlordane, DDT, malathion, captan, heptachlor, diazinon, phorate, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and 2,4-dichlorophenoxyacetic acid (2,4-D). The research suggests that minimizing exposure to some pesticides may decrease the risk of developing AMD. (CN)
Citation: Montgomery MP, Postel E, Umbach DM, Richards M, Watson M, Blair A, Chen H, Sandler DP, Schmidt S, Kamel F. 2017. Pesticide use and age-related macular degeneration in the Agricultural Health Study. Environ Health Perspect 125(7):077013.
Study finds that bedroom allergens are widespread
Exposure to allergens in the home is ubiquitous, according to the nation’s largest indoor allergen study. Using data collected by the 2005-2006 National Health and Nutrition Examination Survey, NIEHS researchers found that allergen exposures in U.S. homes are highly variable and influenced by sociodemographic, regional, climatic, and housing factors.
The research team investigated levels of eight common allergens in the bedrooms of nearly 7,000 homes. More than 90 percent of homes had three or more detectable allergens, and 73 percent had increased levels of at least one allergen. High allergen burden, meaning increased levels of exposure to multiple allergens, was most common in households with pets and pests, mobile homes, old and rental homes, and homes in rural areas.
Allergen exposures showed notable geographic and climatic differences. Increased dust mite allergen levels were more common in the South and Northeast, and in regions with a humid climate. Homes in the South were more likely to have allergens at increased levels, yet the highest number of allergens was detected in the Midwest.
For the first time, researchers compared allergen exposure and sensitization patterns at the national level. Exposure patterns showed distinct differences by sex, race or ethnicity, and level of urbanization. These findings highlighted the complex nature of relationships among allergen exposures, allergic sensitization, and disease. (AR)
Citation: Salo PM, Wilkerson J, Rose KM, Cohn RD, Calatroni A, Mitchell HE, Sever ML, Gergen PJ, Thorne PS, Zeldin DC. 2017. Bedroom allergen exposures in U.S. households. J Allergy Clin Immunol; doi: 10.1016/j.jaci.2017.08.033 [Online 23 November 2017]. (Story)
Polymerase-beta can function as gatekeeper of the mitochondria genome
NIEHS scientists and their collaborators reported that polymerase-beta (Pol-B), in the absence of mitochrondrial aprataxin (APTX) and DNA-building enzymes such as Flap Endonuclease-1 (FEN-1), can perform the function of removing unwanted DNA strands and preserve the accuracy of the mitochondrial genome. APTX normally removes 5’ adenylate (5’ AMP) from DNA ends, unwanted genome ligation groups, and base pair excision repair (BER) intermediates. Therefore, Pol-B can fulfill a protective role by preserving the integrity of mitochondrial DNA repair.
During DNA repair and replication, BER enzymes remove the terminal blocking group known as 5’-adenylated-deoxyribose phosphate (5’dRP). If this process fails, 5’AMP and 5’AMP-dRP can accumulate in the absence of APTX and its cleanup crew. The research team set out to demonstrate whether DNA-binding enzymes, along with APTX, are involved in this process. Using CRISPR/CAS technology, they engineered chicken lymphoma DT40 cells to be deficient in APTX, Pol-B, or both. The mitochondrial extracts from the APTX-deficient cells displayed high Pol-B lyase and FEN 1 excision activities, but low BER levels compared with the cells deficient in both APTX and Pol-B. The scientists concluded that Pol-B can compensate for APTX by removing unwanted BER intermediates, pieces of DNA, and other ligation byproducts from mitochondrial DNA. Pol-B was shown to be a mitochondrial component in a follow-up paper by the group. (PS)
Citation: Caglayan M, Prasad R, Krasich R, Longley MJ, Kadoda K, Tsuda M, Sasanuma H, Takeda S, Tano K, Copeland WC, Wilson SH. 2017. Complementation of aprataxin deficiency by base excision repair enzymes in mitochondrial extracts. Nucleic Acids Res 45(17):10079−10088.
Increased breast cancer risk associated with wood-burning stoves
Based on data from the Sister Study, NIEHS researchers found that burning wood or natural gas in an indoor wood-burning stove or fireplace was associated with a slightly higher risk of developing breast cancer in women. The scientists saw that the increase in risk was highest in women who used a stove or fireplace at least once per week in their home and was most evident in women who lived in the home for more than 10 years. Although the 10-15 percent risk increase is a modest one, the findings suggest that indoor air pollution produced from burning biomass is a potentially modifiable breast cancer risk factor.
The Sister Study examines the environmental and familial risk factors for breast cancer in more than 50,000 healthy women with a sister with breast cancer. After administering detailed questionnaires on indoor heating and cooking practices, and longest adult residence, the research team used Cox regression statistical analysis to determine the association between indoor heating or cooking and breast cancer risk.
The authors stress that indoor air pollution is a major public health issue globally. Some researchers estimate that approximately 2.8 billion people around the world were exposed to this this type of pollution in 2010. This research was the first prospective study to examine the association between indoor stove or fireplace use and breast cancer risk. (HV)
Citation: White AJ, Sandler DP. 2017. Indoor wood-burning stove and fireplace use and breast cancer in a prospective cohort study. Environ Health Perspect 125(7):077011.
(Cody Nichols, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Genetics, Environment, and Respiratory Disease Group. Alicia Richards is a pregraduate fellow in the National Cancer Institute Laboratory of Toxicology and Toxicokinetics. Kelly Shipkowski, Ph.D., is an IRTA fellow in the NTP Systems Toxicology Group. Payel Sil, Ph.D., is an IRTA fellow in the NIEHS Inflammation and Autoimmunity Group. Heather Vellers, Ph.D., is an IRTA fellow in the NIEHS Environmental Genetics Group.)