New approaches to advance cancer hazard evaluations highlighted in commentary

Methodological advancements to address the challenges of traditional cancer hazard evaluations are described in a paper by scientists from the NIEHS Division of Translational Toxicology. According to the authors, new approaches highlighted in recent reports and ongoing evaluations by the National Toxicology Program (NTP) will help to identify and communicate cancer hazards that are contemporary public health concerns.

In December 2021, the congressionally mandated 15th Report on Carcinogens — which was prepared by NTP — was released. New to the report is a Data Exploration Dashboard— an interactive online platform that provides an easy-to-understand visual breakdown of all listed substances. Also, NTP recently published a Cancer Hazard Assessment Report on exposure scenarios associated with circadian disruption: night shift work and light at night. In addition, the program is applying its new approaches to ongoing evaluations.

Such approaches include focusing on real-world exposures, including complex exposures and chemical classes, and advancing methods to address challenges in cancer hazard assessments. For example, NTP is developing more structured approaches to evaluate mechanistic data and incorporating read-across techniques to assess substances that lack adequate human or animal cancer data. And to further promote public health, NTP has provided information on environmental health disparities and disease prevention.

These new directions can increase the transparency and human relevance of cancer hazard evaluations and help inform decision-making at the public health and individual levels. Building on past efforts and incorporating key advancements, NTP aims to continue its contributions to the war on cancer, which was declared 50 years ago, the authors noted.

Citation: Lunn RM, Mehta SS, Jahnke GD, Wang A, Wolfe MS, Berridge BR. 2022. Cancer hazard evaluations for contemporary needs: highlights from new NTP evaluations and methodological advancements. J Natl Cancer Inst; doi:10.1093/jnci/djac164 [Online 27 August 2022].

Shining light on neural circuitry of motivated behavior

Brain cells that play an important role in promoting vigilance also affect feeding behavior in mice and possibly help animals focus their efforts to finding and eating snacks, according to NIEHS researchers and their collaborators.

The ability of the brain to integrate internal physiological drives, such as hunger and satiety, with an ever-changing environment is essential for survival. It is well known that noradrenergic neurons of the locus coeruleus (LC-NE) play a key role in modulating diverse physiological and behavioral states, including arousal, sensory processing, stress, and attention. Yet relatively little is known about the involvement of these cells in the regulation of feeding and the integration of internally driven motivational states.

Using a combination of methods in mice, the researchers found that LC-NE activity was suppressed during food consumption. The magnitude of this neural response decreased as mice ate more pellets, suggesting that LC responses to food were influenced by the level of fullness. The responses of these cells to flashes of light were also attenuated in sated mice.

Taken together, the findings suggest that LC-NE neurons affect feeding by integrating both environmental cues and internal drives. According to the authors, the results demonstrate that fasting enhances LC-NE responses to sensory stimuli, potentially supporting food-seeking and self-preservation activities during foraging.

Citation: Sciolino NR, Hsiang M, Mazzone CM, Wilson LR, Plummer NW, Amin J, Smith KG, McGee CA, Fry SA, Yang CX, Powell JM, Bruchas MR, Kravitz AV, Cushman JD, Krashes MJ, Cui G, Jensen P. 2022. Natural locus coeruleus dynamics during feeding. Sci Adv 8(33):eabn9134.

A constellation of Twinkle structures may have a clinical impact

3D structures of a protein called Twinkle could shed light on mitochondrial diseases in humans, according to NIEHS researchers and their collaborators.

Twinkle is a mammalian enzyme that is vital for the replication and integrity of mitochondrial DNA. More than 90 Twinkle variants have been linked to disorders that are typically characterized by neuromuscular dysfunction. Despite its biological and clinical importance, there had been no atomic models of the enzyme. The lack of high-resolution structural knowledge has hampered a thorough understanding of the molecular mechanisms of Twinkle and associated mitochondrial diseases.

To address this knowledge gap, the researchers used cryo-electron microscopy to determine the full-length structure of the human Twinkle W315L disease variant. They pinpointed the locations of mutations associated with inherited mitochondrial disease, outlining a framework for accurately mapping nearly all clinically identified Twinkle variants.

In addition, the results provide insight into the dynamic movement and molecular consequences of the W315L variant. Taken together, the findings offer a structural basis for the dysfunctional mitochondrial DNA replication that is observed in patients. According to the authors, this study provides a platform for the development of targeted therapies for the treatment of Twinkle-associated mitochondrial diseases.

Citation: Riccio AA, Bouvette J, Perera L, Longley MJ, Krahn JM, Williams JG, Dutcher R, Borgnia MJ, Copeland WC. 2022. Structural insight and characterization of human Twinkle helicase in mitochondrial disease. Proc Natl Acad Sci U S A 119(32):e2207459119.

How environmental exposures may contribute to autoimmunity

A large-scale study in humans reveals potential environmental causes of autoimmunity, according to NIEHS researchers and their collaborators.

The prevalence of autoimmunity in the United States has increased recently for unknown reasons. Although these usually incurable diseases have a large and growing public health impact, the risk factors and mechanisms leading to them remain poorly understood. In particular, the link between environmental causes and autoimmunity has been unclear.

To address this knowledge gap, the researchers analyzed questionnaire data and blood, serum, and urine samples collected from 12,058 participants between 1988 and 2012. According to the authors, this is the largest and most comprehensive study of associations between antinuclear antibodies — the most common clinical biomarkers of autoimmunity — and exposure to chemical substances called xenobiotics, which are not naturally produced or expected to be present in the body.

Of the xenobiotics studied, antinuclear antibodies were positively associated with compounds resembling toxic pollutants known as dioxins, as well as with highly carcinogenic chemicals called polychlorinated biphenyls. In contrast, the results revealed a negative relationship between antinuclear antibodies and most phthalates, which are hormone-disrupting chemicals used to manufacture certain plastics.

Further investigation to confirm these observations and elucidate the underlying mechanisms could have important preventive and treatment implications for a variety of immune disorders, according to the authors.

Citation: Dinse GE, Co CA, Parks CG, Weinberg CR, Xie G, Chan EKL, Birnbaum LS, Miller FW. 2022. Expanded assessment of xenobiotic associations with antinuclear antibodies in the United States, 1988-2012. Environ Int 166:107376.

Crude oil chemicals may increase asthma incidence among cleanup workers

Oil spill cleanup workers had an elevated risk of asthma in the aftermath of the 2010 Deepwater Horizon disaster, according to NIEHS researchers and their collaborators.

The Deepwater Horizon disaster released approximately five million barrels of crude oil into the U.S. Gulf of Mexico. Response and cleanup workers were exposed to airborne contaminants, including a mixture of petroleum hydrocarbons. Little is known about asthma risk among oil spill cleanup workers.

In the largest-ever such study, the researchers assessed the relationship between incident asthma and asthma symptoms and inhalation hazards. The authors analyzed data from 24,937 cleanup workers and 7,671 nonworkers, focusing on those without a pre-spill asthma diagnosis. They leveraged air monitoring and questionnaire data to estimate exposures.

Cleanup workers were more likely than nonworkers to develop asthma in the three years after the oil spill. Increased risk of asthma was associated with exposure to total petroleum hydrocarbons; the hazardous air pollutants benzene, toluene, ethylbenzene, xylene, and hexane (collectively referred to as BTEX-H); and fine inhalable particles produced by burning or flaring oil and gas.

According to the authors, the study provides the first evidence of increased asthma risk associated with exposure to individual crude oil components and the BTEX-H mixture.

Citation: Lawrence KG, Niehoff NM, Keil AP, Braxton Jackson W 2nd, Christenbury K, Stewart PA, Stenzel MR, Huynh TB, Groth CP, Ramachandran G, Banerjee S, Pratt GC, Curry MD, Engel LS, Sandler DP. 2022. Associations between airborne crude oil chemicals and symptom-based asthma. Environ Int 167:107433.