Environmental Factor – May 2020: Inside Papers of the Month

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Written by Aydin Alijo Abdullah, Nicholas Elgna, Arif Rahman, Sania Ratan, and Dahiyat Yu

NTP study: Food coloring byproducts are toxic to breeding mice

Scientists in the Division of the National Toxicology Program (NTP) at NIEHS have shown that 4-methylimidazole (4-MI) can cause toxic effects on the reproduction and development of mice. 4-MI, a chemical by-product of the manufacture of caramel coloring, is found in many products, such as soft drinks, pancake syrup, and coffee. Previous studies have documented its harmful effects in liver and lung tissue, and the International Agency for Research on Cancer, part of the World Health Organization, has classified 4-MI as a probable human carcinogen.

The researchers exposed multiple generations of male and female mice to different doses of 4-MI through their diet. Mice that received 4-MI showed decreased mating, litter production, and number of offspring per litter. These results were associated with three outcomes:

• Exposed male mice and their offspring showed abnormal prostate changes and delayed sperm release.
• Exposed female mice were subjected to birth disturbances.
• Both sexes showed delays in pubertal development after 4-MI exposure.

The lowest dose of 4-MI at which these adverse effects were observed was 750 ppm, equivalent to a daily intake of 50-60 mg per kg of body weight. This study expands knowledge of the potential health risks associated with 4-MI. (DY)

the quote: Behl M, Willson CJ, Cunny H, Foster PMD, McIntyre B, Shackelford C, Shockley KR, McBride S, Turner K, Waidyanatha S, Blystone CR. 2020. Evaluation of multigenerational reproduction of 4-methylimidazole given in the diet of Hsd rats: Sprague Dawley SD. Reprod Toxicol doi: 10.1016 / j.reprotox.2020.03.005 [Online 27 March 2020].

Glucocorticoids play an essential role in the movement of macrophages

Glucocorticoid signaling plays an important role in immune cell locomotion, according to NIEHS scientists and collaborators. Using a human cell line and mouse immune cells, the researchers identified target genes that are involved in cell movement and migration. The identity of target genes and pathways required for immune cell movement can be used in immune cell therapies to augment the immune response.

Glucocorticoid receptors are found in almost all types of immune cells. However, the contribution of glucocorticoids and inflammation to macrophage cells is not fully understood. Macrophages are white blood cells that detect and destroy harmful organisms in the body and play a critical role in inflammation. The scientists used genome-wide microarray combined with ingenuity pathway analysis to identify target genes in macrophages that are activated by glucocorticoid receptors. The team determined that the exopeptidase dipeptidyl peptidase-4 (DPP4) gene is regulated by glucocorticoids in macrophages. Specifically, DPP4 regulation regulates additional proteins involved in macrophage movement and trafficking. Therefore, the scientists were able to link glucocorticoid signals to cell movement in macrophages.

The authors note that these data may help determine why glucocorticoid therapy, although commonly used to suppress chronic inflammation, is less effective in controlling macrophage-dominated inflammatory disorders. (SR)

the quote: Diaz-Jimenez D, Petrillo MG, Busada JT, Hermoso MA, Cidlowski JA. 2020. Glucocorticoids mobilize macrophages by upregulating the exopeptidase DPP4. J Biol Chem 295 (10): 3213-3227.

Gut bacteria and human cells work together to form a key energy molecule

NIEHS researchers have discovered a new symbiotic interaction between mammalian cells and bacteria that promotes nicotinamide adenine dinucleotide (NAD) biosynthesis in host cells. NAD is a cofactor found in all cell types and is essential for life. Low levels of NAD are associated with aging, and high levels of its biosynthesis are important for maintaining the higher metabolic needs of tumors.

In this study, the researchers showed that mycoplasma hyorhinis-infected tumor cell lineages were protected from toxicity by nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which stop NAD biosynthesis. This same effect was observed in vivo, when infected versus uninfected tumor cells were injected into mice. Using a variety of screens and techniques, they showed that this resistance was the result of bacteria providing alternative precursors of NAD to mammalian cells through bacterial nicotinamidase PncA, bypassing the NAMPT-dependent pathway. The authors also demonstrated that PncA is important for the processing of oral nicotinamide supplementation in NAD, indicating that the gut microbiota plays a key role in the biosynthesis of NAD. This study expands the researchers’ understanding of the metabolism of NAD in mammals and the important relationships with the microbiome, opening the door to new therapies. (AAA)

the quote: Shats I, Williams JG, Liu J, Makarov MV, Wu X, Lih FB, Deterding LJ, Lim C, Xu X, Randall TA, Lee E, Li W, Fan W, Li JL, Sokolsky M, Kabanov AV, Li L , Migaud ME, Locasale JW, Li X. 2020. Bacteria promote host NAD metabolism in mammals by engaging the dimer biosynthesis pathway. Cell Metab 31 (3): 564-579.e7. (a story)

Newborn rats for genistein experience pregnancy failures as adults

Using an inbred mouse model, the NIEHS researchers and their collaborators observed that early exposure to genistein after birth caused dysregulation of genes important for female reproductive system differentiation. Previous studies with genistein, a phytoestrogen present in many human soy-based diets, including infant formulas, showed that exposure of newborn mice to genistein caused implantation defects during early pregnancy, leading to sterility.

The present study found that abnormally high expression of Foxa2 during uterine differentiation in newborns likely contributed to implantation failure in mice exposed to genistein. Although the presence of Foxa2 is essential for uterine gland development, its overexpression is associated with decreased glandular formation and complete sterility. The study also showed a decrease in additional genes required for proper uterine growth during the time of exposure, including Sox17 and Wnt4. Previous studies have shown that mice lacking these genes have altered uterine differentiation with decreased numbers of glands and lack of implantation. These data suggest that genistein-induced implant failure is due to altered uterine differentiation that occurs during the time of exposure and causes uterine dysfunction in adults.

Growth of the human uterine gland begins in the fetus but continues after birth until puberty. The results of this research can be used to study women who consumed a soy-based diet in early childhood. (EN)

the quote: Jefferson WN, Padilla-Banks E, Suen AA, Royer LJ, Zeldin SM, Arora R, Williams CJ. 2020. Uterine pattern, endometrial gland development and implantation failure in mice newly exposed to genistein. Environ Health Perspect 128 (3): 37001. (Story)

The association between pain reliever use and female fertility

According to researchers at NIEHS and Duke University, more women who took aspirin around the time of implantation became pregnant than women who did not take aspirin during that time. The scientists conducted the study because they wanted to examine the relationship between fertility, or the likelihood of pregnancy, and use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or acetaminophen. No previous study has examined whether the use of these over-the-counter medications during specific periods of the menstrual cycle affected the ability to become pregnant.

The scientists used statistical analyzes of data collected from a group of women, ages 30 to 44, who all sought pregnancy from 2008 to 2015. The women documented medication use, menstrual window – pre-ovulation, ovulatory status, and implantation – A successful visualization in the daily diary. After examining the data, the researchers found no association between use of acetaminophen or non-aspirin NSAIDs, such as ibuprofen and naproxen, and fertility potential. However, aspirin use during implantation has been associated with increased fertility. Scientists stress the need for clinical trials to confirm these results. (not available)

the quote: Jukic AMZ, Padiyara P, Bracken MB, McConnahey DR, Steiner AZ. 2019. The use of analgesics in ovulation, implantation and human fertility. Am J Obstet Gynecol; doi: 10.1016/j.ajog.2019.11.1251 [Online 15 November 2019].

(Aidin Alejo Abdala is an internal research training award [IRTA] Post-baccalaureate fellow in NIEHS Clinical Investigations for the Host Defense Group. Nicholas Alagna is an IRTA Fellow at NIEHS Mutation Group Mechanisms. Arif Rahman, Ph.D., is a visiting fellow at the NTP Toxicoinformatics Group. Sania Ratan, Ph.D., is an IRTA Fellow in the NIEHS Reproductive Developmental Biology group. Dahea You, MD, PhD, is an IRTA Postdoctoral Fellow in the NTP Group of Molecular Toxicology and Genomics.)

from San Jose News Bulletin https://sjnewsbulletin.com/environmental-factor-may-2020-inside-papers-of-the-month/