Environmental Factor – May 2019: Inside Papers of the Month

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Written by Robin Arnett, Kathleen Foley, Kelly Lennox, Janelle Weaver and King Show

NTP screens chemicals for possible liver injury

When applied to human cell culture models, a high-throughput transcription platform called TempO-Seq captures biological responses to chemicals that cause liver injury, according to a study by researchers at the National Toxicology Program (NTP) and NIEHS-funded colleagues. The new approach may better predict the potentially harmful effects of a wide range of environmental chemicals or pharmaceutical drugs on humans.

Predicting human liver responses to chemical exposures is a major challenge in both pharmacological and toxicological research. To meet this challenge, the researchers used TempO-Seq to generate high-throughput data for approximately 2,700 human transcripts with high contrast. in the laboratory Liver models that were exposed to wide range concentrations of 24 reference compounds. This approach readily distinguishes liver injury compounds, such as the chemotherapeutic drug tamoxifen and pharmaceuticals that have been withdrawn from the market (for example, drug analogues), from compounds that are rarely associated with liver injury, such as caffeine and sucrose.

Furthermore, the authors note the efficient modeling of metabolically active hepatic responses and utilization of the power of a focus-response modeling solution to identify predicted biological response pathways that include hallmarks of liver function. The results showed that high-throughput transcription, along with differentiated in the laboratory Liver models may be an effective tool for modeling, exploring, and interpreting toxicological and drug interactions. (JW)

the quote: Ramaiahgari SC, Auerbach SS, Saddler TO, Rice JR, Dunlap PE, Sipes NS, DeVito MJ, Shah RR, Bushel PR, Merrick BA, Paules RS, Ferguson SS. 2019. Decision Power: Contextual Understanding of Biological Responses to Liver Chemicals Using High Throughput Transcription and Standard Concentration Modeling. Toxicol Sciences. doi: 10.1093/Toxsci/kfz065 [Online 8 March 2019]. (a story)

Pol B maintains its fidelity in the presence of modified cytosines

The precision, or accuracy, of beta DNA polymerase (pol B) is preserved when modified cytosines in the DNA template strand are encountered, according to the NIEHS scientists. As pol B adds new nucleotides to DNA as part of the base excision repair (BER) pathway, understanding how the enzyme handles bulky side chains is important for DNA repair.

The researchers made the discovery by studying how cells remove one form of epigenetic mark, called methyl groups, from their DNA. The removal process uses ten 11 translocation enzymes, BER, to generate three oxidized nucleotide forms of cytosine, or 5-methylcytosine (5mC), which are structurally different: 5-hydroxmethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxycytosine (5 cc). The scientists tested whether these altered polymorphisms affected the ability of pol B to incorporate its nucleotide partner dGTP into the cytosine of DNA.

Using kinetic assays, the scientists showed that 5mC, 5hmC and 5fC did not affect the efficiency of pol B to incorporate dGTP, but when 5caC was in form mode, it reduced the efficiency of pol B 20-fold compared to unmodified cytosine. However, structural studies determined that the backbone of the DNA template was shifted about 2.5 angstroms to avoid collision with the carboxy modification of 5caC. This action allowed urine B to do its job, indicating that epigenetic cytosine modifications were internalized during repair. (RA)

the quote: Howard Mug, Foley kg, Shock Dd, Batra FK, Wilson Sh. 2019. Molecular basis for the honest repeat of 5-methylcytosine and its oxidized forms by DNA polymerase beta. J Byul Chem doi: 10.1074 / jbc.RA118.006809 [Online 18 March 2019].

Abnormal estrogen signals lead to ovarian disorder

NIEHS researchers have revealed that a dysfunction in estrogen signaling may trigger polycystic ovary syndrome (PCOS), a common reproductive problem linked to hormonal imbalance and failure to ovulate in women. The findings provide new insights into the molecular mechanisms of PCOS and infertility.

PCOS is a disorder of the hypothalamic-pituitary-gonadal (HPG) axis, which is tightly controlled by the regulatory feedback loop. In the loop, hypothalamic hormones stimulate the pituitary gland to secrete luteinizing hormone (LH), which stimulates the ovaries to produce estrogen that inhibits the release of hypothalamic hormones. Previous studies have shown that estrogen receptor alpha (ERalpha) is required for HPG regulation, because ERalpha global knockout (ERKO) mice display elevated LH and PCOS phenotypes. In this study, researchers developed a new mouse model (ERalpha-null comprehensive knockout, or PitERtgKO) in which pituitary ERalpha was re-expressed in ERKO mice to investigate the role of pituitary ERalpha in the development of PCOS.

They found that PitERtgKO mice showed a more severe ovarian cystic phenotype than littermates in ERKO littermates, although LH in PitERtgKO mice was restored to a lower level found in wild-type mice. They further determined that intermittent secretion of LH mediated by the pituitary ERalpha, rather than persistently elevated LH, caused severe PCOS phenotypes. (QX)

the quote: Arauway, Hamilton KG, Wu SP, Tsai MG, Dimayo FG, Corach, KS. 2019. Dysregulation of hypothalamic-pituitary estrogen receptor signaling leads to episodic LH secretion and cystic ovaries. FASEB J; doi: 10.1096/fj.201802653RR [Online 13 March 2019].

Shift work associated with epigenetic changes

NIEHS scientists report associations between shift work and changes in DNA methylation patterns that are consistent with long-term health effects. The new study is the first to assess the associations between accelerated epigenetic lifespan and shift work history.

Using methylation data from 2,574 women enrolled in the sister study, the team used established epigenetic clocks to identify women whose estimated genetic age was greater than their chronological age, also known as epigenetic age acceleration. The researchers also measured DNA methylation across the genome. They found that the difference between epigenetic and chronological age was, on average, three years greater for women who worked ten years or more in night-shift jobs than for women who did not work night shifts.

Shift work in general, or working irregular hours or rotating shifts, was more associated with site-specific methylation levels in the ataxin 7 gene, which correlates with susceptibility and prognosis to tumors. Night shift action was also associated with methylation levels at a site within the circadian rhythm gene ZFHX3, which may act as a tumor suppressor. These methylated regions may play a role in the well-known association between shift work and breast cancer. (kuala lumpur)

the quote: White AJ, Kresovich JK, Xu Z, Sandler DP, Taylor JA. 2019. Rosacea functioning, DNA methylation and epigenetic age. Int J Epidemiol; doi: 10.1093.ije/dyz027 [Online 15 March 2019].

Phthalates, oxidative stress, and inflammation in pregnant women

A team led by NIEHS researchers found that alternative metabolites of phthalates and phthalates have associations with the oxidative stress marker 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) that arises from different pathways. The scientists used a novel approach to distinguish 8-iso-PGF2alpha originated through inflammation or oxidative stress. They stress that knowing this information will help determine the overall toxic effects of phthalates on human health and may also help design strategies to mitigate the effects of exposure.

Phthalates are used to soften plastic, but some phthalates have been linked to birth defects. The mechanisms of these relationships are unknown but may involve inflammation and oxidative stress.

The researchers measured 8-iso-PGF2alpha and examined associations with alternate levels of phthalates and phthalates in urine samples from pregnant women in the Infant Development and Environment Study (TIDES). Other scientists from the NIEHS have discovered that both oxidative stress and inflammation can produce 8-iso-PGF2alpha, and these amounts from each pathway can be calculated using the ratio of 8-iso-PGF2alpha to prostaglandin-PGF2alpha (PGF2alpha). In the TIDES study, researchers observed associations between most alternative metabolites of phthalates, phthalates, and 8-iso-PGF2alpha. Using the 8-iso-PGF2alpha/PGF2alpha ratio, they also noted that although most phthalates are associated with the oxidative stress pathway, a specific subset of phthalates with similar structures have associations with the inflammatory pathway. (palm)

the quote: van’t Erve TJ, Rosen EM, Barrett ES, Nguyen RHN, Sathyanarayana S, Milne GL, Calafat AM, Swan SH, Ferguson KK. 2019. Phthalates and phthalates substitutes have diverse associations with oxidative stress and inflammation in pregnant women. Environ Sci-Technol 53 (6): 3258 – 3267.

(Kathleen Foley is a Post-Baccalaureate Fellow in Internship Research Training in the NIEHS Receptor Biology Group. Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison. Cheng Shu is a biologist in the NIEHS Metabolism, Genes and Environment group.)

from San Jose News Bulletin https://sjnewsbulletin.com/environmental-factor-may-2019-inside-papers-of-the-month/