New model helps predict whether chemicals will cause a skin rash

A new machine learning tool allows researchers to predict the potential for human skin to become inflamed in response to chemical agents, according to researchers from the Division of Translational Toxicology.

Skin sensitization testing is used to determine a substance’s potential to cause a skin rash known as allergic contact dermatitis in susceptible individuals. There is an increasing need to quickly determine a compound’s skin sensitization potential from a regulatory standpoint. Unfortunately, these studies are time-consuming and expensive, and they raise ethical concerns.

To more accurately predict how human skin will respond, the researchers carefully curated a human predictive patch test (HPPT) database. The models underwent rigorous validation with reference data, resulting in one of the first in silico tools based strictly on human data for skin sensitization. The high accuracy and sensitivity of the new tool was validated with human biology-based in vitro outcomes and human data.

The rigorously curated data, validation predictions, and models are available on the website. As noted by the researchers, these models can be easily implemented in the early stages of drug development and testing, minimizing resource waste while reducing animal testing. (JW)

Citation: Scheufen Tieghi R, Moreira-Filho JT, Martin HJ, Wellnitz J, Otoch MC, Rath M, Tropsha A, Muratov EN, Kleinstreuer N. 2024. A novel machine learning model and a web portal for predicting the human skin sensitization effects of chemical agents. Toxics 12(11):803.

Social defeat may have lasting effects on a specific brain region

NIEHS researchers and their collaborators have found that a brain region called CA2 plays a key role in how mice respond to social stress, such as social defeat.

The stress response is conserved across species and allows an organism to learn from and adapt to potentially threatening environmental stimuli. Recent studies have highlighted variability in physiological and behavioral effects following exposure to stress. In humans, for example, a traumatic experience can lead to post-traumatic stress disorder (PTSD). Chronic stress has been shown to cause long-lasting changes in the brain, especially in the hippocampus, a region important for memory and emotions.

The researchers investigated whether the hippocampus, specifically area CA2, plays a role in resilience and susceptibility to the stress of an acute social defeat. The results showed that CA2 activity plays a critical role in the lasting effects of social defeat by affecting an animal’s behavior towards an aggressor or their ability to recognize social situations. In addition, the study suggests that an animal’s response to defeat — whether they flee or defend themselves — is a major influence on later avoidance behaviors.

Overall, these data demonstrate that CA2 is important in processing stressful experiences. According to the authors, the findings contribute to the growing understanding of the role that CA2 plays in social behaviors and aggression. (JW)

Citation: Radzicki D, McCann KE, Alexander GM, Dudek SM. 2024. Hippocampal area CA2 activity supports social investigation following an acute social stress. Mol Psychiatry; [doi: 10.1038/s41380-024-02834-9. [Online ahead of print 15 Nov. 2024].

Sunscreen use may affect the immune system of young adults

While broadly protective against skin cancer, sunscreen use may affect the immune system and increase the prevalence of autoimmunity in young adults, according to NIEHS researchers and their collaborators.

Unlike antibodies that target foreign invaders to prevent infection, the immune system can also produce antinuclear antibodies (ANA), which recognize the body’s own cellular components, including DNA. ANA prevalence has significantly increased in the U.S. population. Although the reasons for this increase are not known, sunscreen use has also increased offering one possible clue.

In the current study, the researchers used data from the National Health Examination and Nutrition Survey (NHANES) to evaluate associations between regular sunscreen use and ANA in a sample of adults ages 20-59. The findings showed that frequent use of sunscreen was positively associated with ANA prevalence in U.S. adults aged 20-39, independent of other forms of sun protective behavior or history of sunburns. These findings are consistent with prior findings showing higher urinary concentrations of benzophenone-3 (BP-3), a chemical found in sunscreens, were associated with greater ANA prevalence in some young adults.

The results provide new evidence that sunscreen use may be linked to higher ANA prevalence in young adults, which may have downstream health consequences such as risk for autoimmune diseases. According to the authors, larger, prospective studies are needed to explore the long-term health effects of different types of sunscreens, especially those that are readily absorbed through the skin and may be frequently used, such as cosmetics or other skin care products. (SS)

Citation: Parks CG, Jusko TA, Meier HCS, Wilkerson J, Rider LG, Miller FW, Sandler DP. 2024. Sunscreen use associated with elevated prevalence of anti-nuclear antibodies in U.S. adults. J Autoimmun 149:103340.

A protein called GLIS3 may protect kidney function

The protein GLIS3 plays a protective role in preventing cyst formation, particularly in polycystic kidney disease, according to NIEHS researchers and their collaborators.

Past studies have shown that GLIS3 regulates gene activity and biological functions in the kidney as well as in the pancreas, thyroid, and testis. Mutations in the GLIS3 gene are linked to a syndrome that causes neonatal diabetes, congenital hypothyroidism, and the development of polycystic kidney disease.

In the new study, researchers found that GLIS3 regulates mitochondrial functions and metabolic reprogramming in postnatal kidney development and polycystic kidney disease in mice. Specifically, they identified GLIS3 as a new participant in a complex network that controls the metabolic transition from one type of energy production (aerobic glycolysis) to another (OXPHOS) during the first month of kidney development after birth.

The evidence indicates that GLIS3 directly regulates the expression of many metabolic and mitochondrial function-related genes, while indirectly regulating mitochondria encoded genes. When GLIS3 is not functioning properly, it suppresses the expression of these metabolic genes and promotes features of metabolic reprogramming, causing a shift from OXPHOS to increased aerobic glycolysis. This shift may contribute to the development of polycystic kidney disease.

According to the authors, the study suggests that GLIS3 may help protect the postnatal kidney from cyst formation. They also propose that targeting GLIS3 signaling may offer therapeutic opportunities in the management of polycystic kidney disease. (JW)

Citation: Collier JB, Kang HS, Roh YG, Srivastava C, Grimm SA, Jarmusch AK, Jetten AM. 2024. GLIS3: A novel transcriptional regulator of mitochondrial functions and metabolic reprogramming in postnatal kidney and polycystic kidney disease. Mol Metab 90:102052.

Targeting Flotillin-2 may boost immune protection

A protein called Flotillin-2 plays a role in regulating T-cell responses, which are crucial for immune protection. This discovery could potentially be leveraged therapeutically, according to NIEHS researchers and their collaborators.

Proper regulation of T-cell receptor (TCR) activation is essential for effective immunity, but how T cells manage this process remains unclear. Moreover, the role of membrane proteins such as Flotillin-2 in T-cell responses needs to be clarified, especially in terms of their potential for therapeutic use.

The team found that mice specifically lacking Flotillin-2 in T cells showed slower tumor growth and better resistance to Listeria infection associated with enhanced T-cell proliferation and cytokine production. T cells lacking Flotillin-2 also had stronger activation of their receptors, even with weak stimulation. These T cells showed a lower threshold for TCR activation. Super-resolution imaging revealed that Flotillin-2 may control clustering of TCR molecules, affecting the sensitivity of T cells to the environment.

According to the authors, these findings suggest that targeting Flotillin-2, either directly or by engineering T cells for adoptive cell therapy, could improve T-cell activity. This approach may hold promise for treating diseases such as cancer and chronic infections by enhancing immune responses. (JW)

Citation: Moon S, Zhao F, Uddin MN, Tucker CJ, Karmaus PW, Fessler MB. 2024. Flotillin-2 dampens T cell antigen-sensitivity and functionality. JCI Insight 9(24):e182328.