NTP finds arsenic exposure leads to a mutated KRAS allele

National Toxicology Program (NTP) researchers showed that arsenic-induced transformation of a human prostate cell line is driven by a mutant form, called an allele, of KRAS acting as an oncogene that increases cell proliferation. Sequencing of KRAS showed a mutant-specific allelic imbalance frequently seen in primary clinical tumors. These findings revealed molecular mechanisms underlying arsenic-mediated cancer formation.

Arsenic is a well-known environmental carcinogen found in the soil, water, air, and food. Long-term exposure to arsenic has been associated with many cancers, including prostate cancer. NTP researchers previously developed a malignant invasive prostate cancer cell line (CAsE-PE) by long-term, low-level arsenic exposure of a non-tumorigenic human prostate epithelial cell line (RWPE-1). In this study, they performed RNA-Seq and targeted sequencing analysis of both cell lines to identify changes of genes and pathways that may contribute to arsenic-induced carcinogenesis.

Thousands of genes were differentially expressed in CAsE-PE cells compared with parental RWPE-1 cells, with many involved in cell growth and cancer development. CAsE-PE cells substantially overexpressed a mutated and oncogenic KRAS variant commonly seen in tumor cells, which suggested arsenic exposure could lead to accumulation of KRAS mutations, driving transformation of normal cells to cancer. How arsenic causes KRAS overexpression is currently under investigation. (QX)

Citation: Merrick BA, Phadke DP, Bostrom MA, Shah RR, Wright GM, Wang X, Gordon O, Pelch KE, Auerbach SS, Paules RS, DeVito MJ, Waalkes MP, Tokar EJ. 2019. Arsenite malignantly transforms human prostate epithelial cells in vitro by gene amplification of mutated KRAS. PLoS One 14(4):e0215504.

DNA methylation changes occur years before breast cancer develops

Scientists at NIEHS determined that women who develop breast cancer exhibit methylation differences in their blood DNA years before the tumors are clinically detected. DNA methylation is an epigenetic modification in which methyl groups bind to DNA, potentially altering gene expression. The study identified differentially methylated DNA sites that offer the potential for improved early breast cancer diagnosis.

The authors assessed DNA methylation profiles in blood samples collected from 2,443 women at the time they enrolled in the Sister Study, an NIEHS prospective study of women who have a biological sister with breast cancer. The scientists identified 9,601 sites that were differentially methylated between women who developed breast cancer during follow-up and those who remained breast cancer free. Validating their findings, 2,095 of these differentially methylated sites were replicated in an independent study, and 42 of the methylation sites were located near known breast cancer susceptibility genes. Differential methylation was more apparent for women who developed breast cancer in the first few years after study enrollment.

The authors suggest these changes may reflect the body’s response to an occult tumor in the years before the cancer becomes clinically apparent. Although the methylation changes are small, together the large number of altered sites could be a useful component in screening for early invasive breast cancer. (ML)

Citation: Xu Z, Sandler DP, Taylor JA. 2019. Blood DNA methylation and breast cancer: a prospective case-cohort analysis in the Sister Study. J Natl Cancer Inst; doi: 10.1093/jnci/djz065 [Online 15 April 2019].

Phytoestrogens may control obesity by regulating PPAR-gamma

Compounds that naturally occur in plants, known as phytoestrogens, may have a role in obesity, according to a team led by NIEHS researchers. The scientists show that these compounds may regulate the activity of peroxisome proliferator-activated receptor gamma (PPAR-gamma), a nuclear receptor that is a key player in storing fat, also known as adipogenesis. Phytoestrogens have been shown to bind to PPAR-gamma and alter its signaling function, thereby disrupting downstream processes.

To better understand the effects of phytoestrogens on obesity, the authors looked at the effects of resveratrol and the soy isoflavones genistein and daidzein. Specifically, they set out to look at the impact of these compounds on PPAR-gamma signaling and response. Using cell-based assays and quantitative polymerase chain reaction, they observed different effects based on the compound used. Resveratrol showed adverse effects on adipogenicity, whereas the soy isoflavones showed positive effects. These results showed that PPAR-gamma should be considered for use as an indicator to screen dietary components and identify compounds with adipogenic activities. (SS)

Citation: Hall JM, Powell HA, Rajic L, Korach KS. 2019. The role of dietary phytoestrogens and the nuclear receptor PPARgamma in adipogenesis: an in vitro study. Environ Health Perspect 127(3):37007.

Possible treatment for heart disease targets stress hormone receptors

A team led by NIEHS researchers have discovered that balancing the activity of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), two proteins associated with stress, could lead to more effective therapies for treating heart disease. Heart disease remains a leading cause of death in the United States, and stress is increasingly associated with pathways that lead to it.

To identify how these stress hormone receptors affect the heart, the team made three mice models: one without GR, one without MR, and one without either receptor in heart tissue. They discovered that mice without GR developed an enlarged heart, experienced heart failure, and died prematurely, whereas mice without MR had normal, healthy hearts. The mice without GR and MR had slightly larger hearts, but with normal function. When the scientists ran a gene expression analysis, they found that the mice in the latter group not only lacked gene changes that lead to heart failure in the mice without GR, but also presented with unique cardioprotective gene changes. Developing therapies that favor GR activity and less MR activity could lead to a better treatment for combating or preventing heart disease. (SK)

Citation: Oakley RH, Cruz-Topete D, He B, Foley JF, Myers PH, Xu X, Gomez-Sanchez CE, Chambon P, Willis MS, Cidlowski JA. 2019. Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice. Sci Signaling; doi: 10.1126/scisignal.aau9685 [Online 16 April 2019]. (Story)

Environmental styrene exposure and neurological function

NIEHS researchers and their collaborators found that environmental exposure to styrene, a chemical compound found in car tires, Styrofoam, plastic cups, cigarette smoke, and traffic and industrial emissions, may be associated with impaired visual and sensory function. This finding suggests that even relatively low levels of styrene may have neurotoxic effects.

Styrene, at occupational exposure levels, is known to be a neurotoxicant that affects the central nervous system. Effects on peripheral nervous system function are less clear. Furthermore, previous studies primarily focused on workers who were exposed to high levels of styrene, leaving the effect of long-term, low-level exposure unknown. To address these questions, scientists estimated ambient styrene exposure levels for 3,000 participants from the Gulf States enrolled in the Gulf Long-term Follow-up Study who had completed a comprehensive testing battery to evaluate their sensory and motor function. Blood styrene levels were measured for a subset of these participants.

Results showed that participants with higher styrene exposure levels had worse visual and sensory function, as well as poorer balance. Their voluntary motor performance was not affected. Future research is needed to determine if these styrene-associated impairments are chronic in nature, and whether they indicate future risk of developing neurological disorders. (YWC)

Citation: Werder EJ, Sandler DP, Richardson DB, Emch ME, Kwok RK, Gerr FE, Engel LS. 2019. Environmental styrene exposure and sensory and motor function in Gulf Coast residents. Environ Health Perspect 127(4):47006.