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Papers of the Month

Intramural
By Ketrell McWhorter, Ravikanth Velagapudi, Heather Vellers, Frieda Wiley, and Qing Xu

NTP workshop focuses on dietary botanical supplements

To address the challenges of assessing the safety of botanical dietary supplements, the National Toxicology Program (NTP) convened a workshop in 2016 called, "Addressing Challenges in the Assessment of Botanical Dietary Supplement Safety." The discussions and outcomes of the meeting were published in the journal Food and Chemical Toxicology.

Botanical dietary supplements, sometimes called herbals or herbal dietary supplements, are products made from plants, plant parts, or plant extracts. According to estimates from one group, Americans spent approximately $7.5 billion on these supplements in 2016. Due to their widespread use, but lack of toxicity data on these products, NTP invited stakeholders involved in research, manufacturing, regulation, and consumption of the products to the workshop. The meeting prioritized three challenges in evaluating botanical safety: developing methods to compare botanical products that display a high degree of variability; identifying active ingredients responsible for biological responses to botanicals; and assessing the way the body absorbs, distributes, metabolizes, and eliminates botanicals.

Workshop participants discussed inconsistencies in study design and product composition, as well as difficulty in evaluating toxicity and maintaining product quality and integrity. They also addressed regulatory issues, including mandatory new dietary ingredient notifications. The meeting also highlighted the roles of the National Center for Complementary and Integrative Health and the U.S. Food and Drug Administration’s Office of Dietary Supplement Program in these efforts. (KM)

Citation: Shipkowski KA, Betz JM, Birnbaum LS, Bucher JR, Coates PM, Hopp DC, MacKay D, Oketch-Rabah H, Walker NJ, Welch C, Rider CV. 2018. Naturally complex: perspective and challenges associated with Botanical Dietary Supplement Safety assessment. Food Chem Toxicol; doi: 10.1016/j.fct.2018.04.007 [Online 4 April 2018].

Patterns of personal care product use and breast cancer in women

Moderate or frequent use of beauty products may be associated with an increased risk of breast cancer in women, according to researchers from NIEHS and the University of North Carolina at Chapel Hill. The team used data from the Sister Study, a prospective study of environmental and genetic risk factors for breast cancer. The findings are consistent with evidence from animal and laboratory studies, which suggest that the estrogen-mimicking chemicals in these products, such as phthalates and phenols, are associated with breast cancer risk.

More than 50,000 women in the U.S. and Puerto Rico, aged 35-74 years with at least one sister diagnosed with breast cancer, enrolled in the study. Participants completed questionnaires about their environmental and reproductive exposures, including use of personal care products.

The researchers studied patterns of use of three types of personal care products — beauty, skin, and hair. Although moderate and frequent users of beauty and frequent users of skincare products had an increased risk of breast cancer relative to infrequent users, the hair products studied were not associated with breast cancer. The authors stressed that this study did not address specific products or chemicals, but rather correlated product-use patterns. (RV)

Citation: Taylor KW, Troester MA, Herring AH, Engel LS, Nichols HB, Sandler DP, Baird DD. 2018. Associations between personal care product use patterns and breast cancer risk among white and black women in the Sister Study. Environ Health Perspect 126(2):027011.

DES reprograms development of mouse uterus

NIEHS researchers have revealed that the synthetic estrogen diethylstilbestrol (DES) can cause epigenetic changes and alter gene expression in the developing mouse uterus. The findings provide a crucial mechanism for the detrimental effects of estrogenic endocrine disruptors on development of the female reproductive system.

DES, once prescribed clinically to treat pregnancy complications, was found to induce abnormal uterine structure and function, as well as to increase cancer risk. The authors hypothesized that developmental exposure to DES affects the epigenome of the reproductive tract and results in permanent altered gene expression that contributes to poor reproductive health outcomes, including cancer.

To test the hypothesis, the researchers exposed neonatal female mice to DES and analyzed the histone modifications of the uterine epigenome. They found that genes that were changed by DES had increased signals of histone mark H3K27ac at their gene regulatory regions, including both the promoters and the enhancers. DES-dependent active enhancers were enriched with the binding sites for estrogen receptor alpha (ER alpha), a transcriptional factor activated by estrogen. Deletion of ER alpha in the uterus abolished DES-mediated changes of the H3K27ac signal and corresponding gene expression. The results suggested that ER alpha is essential for the epigenetic modifications and transcriptional activation caused by DES. (QX)

Citation: Jefferson WN, Kinyamu HK, Wang T, Miranda AX, Padilla-Banks E, Suen AA, Williams CJ. 2018. Widespread enhancer activation via ERalpha mediates estrogen response in vivo during uterine development. Nucleic Acids Res; doi: 10.1093/nar/gky260 [Online 10 April 2018].

Mitochondrial dysfunction linked to nuclear DNA methylation

NIEHS researchers and their collaborators at Northwestern University Feinberg School of Medicine recently discovered a connection between mitochondrial function and epigenetics. They found that mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with metabolism of the amino acid methionine and the epigenetic regulation of nuclear gene expression. The TCA cycle is a crucial mitochondrial biochemical process responsible for cellular energy production. The work offers a pathway for a broader understanding of the impact of mitochondrial dysfunction in health and disease, including the biological consequences of environmental toxicants that target the mitochondria.

Using a cell culture model of induced mitochondrial DNA depletion to initiate a progressive loss of mitochondrial respiration, the scientists utilized techniques to measure gene expression, metabolites, and DNA methylation, which is an epigenetic modification intimately associated with the regulation of gene expression. They also incorporated advanced bioinformatic methods in their work.

The researchers determined that progressive loss of mitochondrial function led to an alteration in nuclear gene expression associated with changes in DNA methylation. Such changes were reversed once homeostasis of NADH oxidation was restored in the mitochondria. Taken together, these findings demonstrated a novel link between mitochondrial function and epigenetic regulation of gene expression that involved changes in the TCA cycle and altered amino acid metabolism. (HV)

Citation: Lozoya A OA, Martinez-Reyes I, Wang T, Grenet D, Bushel P, Li J, Chandel N, Woychik RP, Santos JH. 2018. Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation. PLoS Biol 16(4):e2005707.

Altering neuronal activity patterns changes gene expression

Researchers from NIEHS, Harvard Medical School, and the University of California Merced determined that the history of neuronal activity patterns in the brain can be deduced by looking at gene expression profiles. The finding will help scientists better understand how the brain engages with the environment.

Members of the research team used genome-scale technology to compare gene induction, or the turning on of genes, in response to brief and sustained neuronal activity patterns. They found that brief activity can induce a subset of activity-regulated genes (ARGs) that correlates with the first of three waves of ARGs induced by sustained activity. First-wave ARGs are induced rapidly, require the calcium-dependent signaling pathway MAPK/ERK, and do not need the production of new proteins, known as de novo translation. In contrast, latter-wave ARGs are induced more slowly, do not need MAPK/ERK, but do need de novo translation.

MAPK/ERK establishes multi-wave structure of gene induction and enables activity-duration-specific gene induction. In other words, the same mechanisms that establish rapid and slow gene responses also allow different genes to be induced by different durations of activity. (FW)

Citation: Tyssowski KM, DeStefino NR, Cho JH, Dunn CJ, Poston RG, Carty CE, Jones RD, Chang SM, Romeo P, Wurzelmann MK, Ward JM, Andermann ML, Saha RN, Dudek SM, Gray JM. 2018. Different neuronal activity patterns induce different gene expression programs. Neuron 98(3):530-546.e11.

(Ketrell McWhorter, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Social and Environmental Determinants of Health Equity Group. Ravikanth Velagapudi, Ph.D., is a visiting fellow in the NIEHS Neuropharmacology Group. Heather Vellers, Ph.D., is an IRTA fellow in the NIEHS Environmental Genetics Group. Frieda Wiley, D. Pharm., is a contract writer for the NIEHS Office of Communications and Public Liaison. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)