NTP study: Food coloring byproduct is toxic to rat reproduction

Scientists in the Division of the National Toxicology Program (NTP) at NIEHS have demonstrated that 4-methylimidazole (4-MI) can cause toxic effects to rat reproduction and development. 4-MI, a chemical that is a byproduct of caramel coloring manufacturing, is found in various products, such as carbonated beverages, pancake syrup, and coffee. Previous studies have documented its adverse 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 possible human carcinogen.

Researchers exposed multiple generations of male and female rats to different doses of 4-MI via their diet. Rats that received 4-MI displayed a reduction in mating, producing litters, and number of offspring per litter. Such findings were associated with three outcomes:

• Exposed male rats and their offspring displayed abnormal changes in the prostate and delayed sperm release.
• Exposed female rats experienced disturbances in giving birth.
• 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 parts per million, equivalent to a daily intake of 50-60 mg per kg of body weight. This study expands the knowledge of potential health risks associated with 4-MI. (DY)

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

Glucocorticoids serve an essential role in macrophage mobility

Glucocorticoid signaling plays a critical role in immune cell mobility, according to NIEHS scientists and their collaborators. By using a human cell line and mouse immune cells, the researchers identified target genes that participate in cell mobility and migration. The identity of target genes and pathways necessary for immune cell mobility may be used in immune cell therapies to increase immune response.

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

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

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

Gut bacteria, human cells work together to make key energy molecule

NIEHS researchers discovered a novel symbiotic interaction between mammalian cells and bacteria that boosts nicotinamide adenine dinucleotide (NAD) biosynthesis in host cells. NAD is a cofactor that exists in all cell types and is necessary for life. Decreased levels of NAD are associated with aging, and elevated levels of its biosynthesis are important to sustain the higher metabolic needs of tumors.

In this study, researchers showed that cancer cell lines infected with Mycoplasma hyorhinis were protected against toxicity by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, which halt NAD biosynthesis. This same effect was observed in vivo, when infected versus non-infected cancer cells were injected in mice. Using a variety of screens and techniques, they showed that this resistance was a result of bacteria providing alternative NAD precursors to mammalian cells through the bacterial nicotinamidase PncA, bypassing the NAMPT dependent pathway. Researchers also showed that PncA is important to processing oral nicotinamide supplements into NAD, indicating that gut microbiota play a key role in NAD biosynthesis. This study widens researchers’ understanding of NAD metabolism in mammals and the important relationships with the microbiome, opening the door to new therapeutics. (AAA)

Citation: 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 J-L, Sokolsky M, Kabanov AV, Li L, Migaud ME, Locasale JW, Li X. 2020. Bacteria boost mammalian host NAD metabolism by engaging the deamidated biosynthesis pathway. Cell Metab 31(3):564−579.e7. (Story)

Mice neonatally exposed to genistein have pregnancy failures as adults

Using an in-house mouse model, NIEHS researchers and their collaborators observed that early postnatal genistein exposure caused dysregulation of genes important for female reproductive tract differentiation. Previous studies with genistein, a phytoestrogen found in many soy-based human diets, including infant formulas, showed that neonatal exposure of mice to genistein caused defects in embryo implantation during early pregnancy, leading to infertility.

The current study found that abnormally high expression of Foxa2 during neonatal uterine differentiation most likely contributed to implantation failure in genistein-exposed mice. Although presence of Foxa2 is essential for uterine gland development, overexpression is associated with reduced gland formation and complete infertility. The study also showed reductions in additional genes required for proper uterine development during the time of exposure, including Sox17 and Wnt4. Previous studies showed that mice lacking these genes have altered uterine differentiation with reduced gland numbers and implantation deficits. These data suggest that genistein-induced implantation failure is due to altered uterine differentiation that occurs during the time of exposure and causes adult uterine dysfunction.

Human uterine gland development starts in the fetus but continues postnatally until puberty. The results of this research may be used to study women who consumed a soy-based diet in early childhood. (AR)

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

Association between pain reliever use and female fertility

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

The scientists employed statistical analyses of data gathered from a cohort of women, ranging from 30 to 44 years of age, who all sought to conceive from 2008 to 2015. The women documented medication use, menstrual cycle windows — preovulatory, periovulatory, and implantation — and successful conception in daily diaries. After examining the data, the researchers did not find an association between the use of acetaminophen or non-aspirin NSAIDs, such as ibuprofen and naproxen, and fecundability. However, aspirin use during the implantation period was associated with increased fecundability. The scientists stress that clinical trials should be undertaken to confirm these results. (NA)

Citation: Jukic AMZ, Padiyara P, Bracken MB, McConnaughey DR, Steiner AZ. 2019. Analgesic use at ovulation and implantation and human fertility. Am J Obstet Gynecol; doi: 10.1016/j.ajog.2019.11.1251 [Online 15 November 2019].