Papers of the Month
By Sara Amolegbe
NRF2 activation leads to enlarged liver
An NIEHS-funded study suggested that prolonged activation of a protein nuclear factor called erythroid 2-related factor 2 (NRF2) may contribute to liver enlargement and fatty liver diseases. Normally, NRF2 plays an important role in regulating antioxidant defenses. In this study, researchers found that NRF2 also activated a protein called AKT, which is involved in glucose metabolism and other cell processes, and led to persistent production of growth factors associated with liver enlargement.
When cells are healthy and unstressed by oxidants, NRF2 is generally kept low by a protein called kelch-like ECH-associated protein 1 (KEAP1). However, oxidative stress leads to inactivation of KEAP1, so NRF2 levels build up within a cell. Using a new mouse model with liver cells that express a KEAP1-resistant form of NRF2, the researchers studied what happens when NRF2 was persistently activated. Without KEAP1 to regulate NRF2, the researchers found rapid liver enlargement, known as hepatomegaly.
NRF2-induced hepatomegaly is similar to hepatomegaly induced by too much insulin, in a process that relies on activation of AKT. So the research team investigated the involvement of insulin and AKT in NRF2-induced hepatomegaly. Although they found no evidence for excessive insulin production, AKT was activated in mouse livers and played a key role in the hepatomegaly process.
The scientists also discovered that inhibiting AKT completely reversed hepatomegaly and restored normal liver size and physiology in mice. According to the authors, the finding suggested that AKT inhibitors, which have already been evaluated in humans for their anti-cancer activity, may potentially be used for treating and reversing hepatomegaly.
Citation: He F, Antonucci L, Yamachika S, Zhang Z, Taniguchi K, Umemura A, Hatzivassiliou G, Roose-Girma M, Reina-Campos M, Duran A, Diaz-Meco MT, Moscat J, Sun B, Karin M. 2020. NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly. J Hepat; doi: 10.1016/j.jhep.2020.01.023 [Online 24 Feb 2020].
XPA protein bends DNA and locates DNA damage
NIEHS grantees found that a protein known as XPA bends DNA and pauses in response to DNA damage, revealing the location of damaged DNA and potentially promoting the recruitment of DNA repair proteins. Using single molecule experiments and imaging techniques, the researchers observed the biochemistry in a living cell, providing insight into a new damage sensor role for XPA.
XPA is known to play a role in nucleotide excision repair (NER), a type of DNA repair that removes a wide range of DNA lesions, including damage caused by ultraviolet light. However, how XPA contributes to NER and whether it has a role in recognizing damage is not well understood. The researchers used a new method to calculate the molecular weight of small proteins bound to DNA and tracked proteins involved in DNA repair in 3D using real-time single molecule imaging.
The findings suggested that different forms of XPA were associated with different phases of movement along DNA. XPA cycled through three distinct states on DNA: rapidly hopping over long distances of the DNA strand, slowly sliding over short ranges of DNA while bending local DNA regions, and pausing and forming complexes with bent DNA. XPA paused more frequently in the presence of more DNA damage.
According to the authors, their data are consistent with a model in which XPA bends DNA to search for lesions and pauses in response to DNA damage, signaling the location of damaged DNA to promote recruitment of additional proteins to repair the DNA.
Citation: Beckwitt EC, Jang S, Detweiler IC, Kuper J, Sauer F, Simon N, Bretzler J, Watkins SC, Carell T, Kisker C, Van Houten B. 2020. Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search. Nature Commun 11:1356.
Racial disparities in chemical exposures for U.S. women
NIEHS grantees identified striking differences in markers of chemical exposure for women of different races and ethnicities, independent of other demographic factors. According to the authors, the findings shed light on the environmental factors that may drive racial disparities in disease outcomes.
The researchers conducted a comprehensive analysis of chemical exposures by race and ethnicity in 38,080 U.S. women. They studied biomarker data for 143 chemicals collected by the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2014. The scientists adjusted for age, socioeconomic status, smoking habits, and the cycle of NHANES data collection.
Compared with non-Hispanic white women, they observed higher overall biomarker levels of several chemicals among non-Hispanic black, Mexican American, other Hispanic, and other race or multiracial women. Specifically, these women had higher levels of pesticides and their metabolites, compounds associated with personal care and consumer products, such as parabens and monoethyl phthalate, and several metals, including mercury and arsenic. Average differences in chemical biomarker concentrations between race and ethnic groups exceeded 400% for paraben metabolite comparisons between young non-Hispanic black and non-Hispanic white women.
Metals, pesticides, and chemicals in consumer products showed the highest disparities of the chemicals studied. Some, like the metabolites of pesticides that contain dichlorophenol, persisted across age groups. According to the authors, the findings could help prioritize chemicals when designing studies and help guide public health interventions to reduce environmental and health disparities across populations.
Citation: Nguyen VK, Kahana A, Heidt J, Polemi K, Kvasnicka J, Jolliet O, Colacino JA. 2020. A comprehensive analysis of racial disparities in chemical biomarker concentrations in United States women, 1999-2014. Environ Int 137:105496.
High levels of PFAS in Cape Fear River striped bass
NIEHS grantees found elevated levels of 11 per- and polyfluoroalkyl substances (PFAS) in the blood of Cape Fear River striped bass. The higher levels were associated with markers of altered immune and liver functions in the fish.
The team isolated serum from the blood of 58 wild striped bass caught in North Carolina’s Cape Fear River. The fish ranged in age from 2 to 7 years. Using a combination of liquid chromatography and high-resolution mass spectrometry, the researchers determined concentrations of 23 different PFAS chemicals present in serum. Results from the wild caught fish were compared with those from a reference population of 29 striped bass raised in an aquaculture facility that was fed by groundwater.
The average total PFAS concentrations in the wild caught bass were 40 times higher than the levels found in the reference population. Elevated levels of two of the PFAS chemicals, perfluorooctane sulfonate and Nafion byproduct 2, were found in 100% and 78% of the wild bass samples, respectively, compared with levels in Cape Fear River water. The serum concentrations of these compounds were associated with biomarkers of altered liver enzyme activity and immune function.
Unexpectedly, smaller fish had the highest levels of these chemicals. This finding suggests that PFAS may have different chemical properties than mercury and other chemicals that bioaccumulate. Such chemicals are often found at higher levels in larger fish. According to the authors, further studies are needed to define the specific factors influencing exposure, bioaccumulation, and the resulting adverse impacts of PFAS in fish.
Citation: Guillette TC, McCord J, Guillette M, Polera ME, Rachels K, Morgeson C, Kotlarz N, Knappe DRU, Reading BJ, Strynar M, Belcher SM. 2020. Elevated levels of per- and polyfluoroalkyl substances in Cape Fear River Striped Bass (Morone saxatilis) are associated with biomarkers of altered immune and liver function. Environ Int 136:105358.
(Sara Amolegbe is a research and communication specialist for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)