Papers of the Month
By Aidin Alejo Abdala, Nicholas Alagna, Mimi Huang, Arif Rahman, Janelle Weaver
NTP Ginkgo biloba study reports molecular profile of mouse liver tumors
A recent study performed by Division of National Toxicology Program (NTP) scientists revealed abnormal microRNA (miRNA) expression patterns in murine hepatocellular carcinomas (HCC) associated with exposure to Ginkgo biloba extract (GBE). miRNAs are regulators of gene expression that play a role in cancer. According to the authors, this study is the first to assess global miRNA expression in murine HCC following long-term chemical exposure.
The NTP previously showed a dose-dependent increase in HCC in B6C3F1/N mice after two years of exposure to GBE. To determine the potential involvement of miRNAs in GBE-induced murine HCC, the researchers conducted global miRNA expression analysis in four types of tissue derived from B6C3F1/N mice: spontaneously occurring HCC (SPNT-HCC); GBE-exposed HCC (GBE-HCC); GBE-exposed nontumor samples; and age-matched normal livers not exposed to GBE.
Compared with normal livers, GBE-HCC had 74 differentially expressed miRNAs and SPNT-HCC had 33. Moreover, the findings for a miRNA called miR-31suggested a post-transcriptional effect. Some miRNAs that were altered in GBE-HCCs were also altered in nontumor samples from livers exposed to GBE for 90 days. These findings suggest that miRNAs could serve as biomarkers of disease or exposure. (NA)
Citation: Yamashita H, Surapureddi S, Kovi RC, Bhusari S, Ton TV, Li JL, Shockley KR, Peddada SD, Gerrish KE, Rider CV, Hoenerhoff MJ, Sills RC, Pandiri AR. 2020. Unique microRNA alterations in hepatocellular carcinomas arising either spontaneously or due to chronic exposure to Ginkgo biloba extract (GBE) in B6C3F1/N mice. Arch Toxicol; doi: 10.1007/s00204-020-02749-8 [Online 18 April 2020].
Preeclampsia and a child’s brain development
The risk of various neurodevelopmental disorders is higher in the children of mothers who experienced a serious vascular condition called preeclampsia during pregnancy, according to a study by NIEHS researchers.
Preeclampsia causes a sudden increase in maternal blood pressure after the 20th week of pregnancy. Past research has shown that the children of mothers with preeclampsia are more likely to have cerebral palsy, which is a group of neurological disorders that cause permanent movement problems. Moreover, preeclampsia increases the risk that children will develop autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, it has not been clear whether children of mothers with preeclampsia are also more likely to have other neurodevelopmental disorders.
To help fill this knowledge gap, the researchers examined the incidence of neurodevelopmental disorders in children up to five years of age using Norwegian data from 980,560 full-term births between 1991 and 2009. Consistent with previous research, they found that preeclampsia was associated with an increased risk of cerebral palsy, ASD, and ADHD. In addition, the study expanded the list of possible effects of preeclampsia to include epilepsy and intellectual disability. The research could lead to the discovery of prenatal biomarkers that clinicians could use to intervene for the benefit of child health. (JW)
Citation: Sun BZ, Moster D, Harmon QE, Wilcox AJ. 2020. Association of preeclampsia in term births with neurodevelopmental disorders in offspring. JAMA Psychiatry; doi: 10.1001/jamapsychiatry.2020.0306 [Online 1 April 2020]. (Story)
Mutation associated with breast cancer can promote tumor growth
A patient-derived mutation in the transcription factor GATA3 plays an important role in estrogen receptor alpha (ER-alpha) positive breast tumors, according to NIEHS researchers and their collaborators. Transcription factors are proteins that regulate gene expression. Mutations in these proteins have been identified in many tumors, but their functional consequences are largely unknown. Understanding how transcription factor mutations can influence cancer development has clinical implications related to cancer risk.
NIEHS researchers studied the effect of a specific mutation in GATA3 that has been observed repeatedly in breast tumors. GATA3, in conjunction with ER-alpha and transcription factor FOXA1, regulates genes essential for mammary gland development. In the new study, this mutation in GATA3 changed the distribution of ER-alpha and FOXA1 throughout the genome of human mammary gland epithelial cells. Specifically, there was reduced binding of these transcription factors at genes that maintain expression of markers on epithelial cells that ensure the cells remain as epithelial cells. Consequently, cells with mutant GATA3 express less epithelial cell markers and have a more cancerous phenotype. It is likely that other impairments in the regulatory activity of the three transcription factors — GATA3, ER-alpha, FOXA1 — contribute to the development of more aggressive breast tumors in cells and in vivo. (MH)
Citation: Takaku M, Grimm SA, De Kumar B, Bennett BD, Wade PA. 2020. Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by estrogen receptor alpha, FOXA1 and GATA3. Nucleic Acids Res 48(9):4756–4768.
Prevalence of autoimmunity marker is on the rise in the U.S.
An NIEHS study reported a concerning rise in the prevalence of antinuclear antibodies (ANAs), which are commonly used biomarkers for autoimmunity. ANAs are produced by a person’s own immune system and attack healthy cells. This is the first study to evaluate ANA changes over time in a representative sampling of the U.S. population. The findings may indicate an increase in autoimmune diseases.
Using the National Health and Nutrition Examination Survey (NHANES), team members analyzed serum ANAs in 14,211 participants aged 12 years and older from three time periods. ANA prevalence increased as follows.
- 11% from 1988 to 1991.
- 11.5% from 1999 to 2004.
- 15.9% from 2011 to 2012.
The researchers found the largest ANA increases in adolescents, males, non-Hispanic whites, and adults older than 50 years compared with other subgroups. The association between the increases and commonly suspected risk factors, such as obesity, smoking, and alcohol consumption, was inconclusive. The authors plan new studies to identify the driving forces behind ANA increases and develop predictive models and preventative strategies for autoimmune diseases. (AR)
Citation: Dinse GE, Parks CG, Weinberg CR, Co CA, Wilkerson J, Zeldin DC, Chan EKL, Miller FW. 2020. Increasing prevalence of antinuclear antibodies in the United States. Arthritis Rheumatol; doi: 10.1002/art.41214 [Online 7 April 2020]. (Story)
Patients without a nose provide insight on development of certain neurons
By studying patients with arhinia, or those born without a nose, NIEHS scientists and their collaborators discovered that gonadotropin-releasing hormone (GnRH) neurons may not depend on olfactory, or smell, structures to reach the brain. GnRH neurons are essential for normal reproductive development in humans and have a unique birthplace: these cells originate in the primitive nose of the fetus before they move to the brain later in gestation. The work helps researchers understand some principles of human development.
The team studied 11 patients with congenital arhinia from across the U.S. and obtained detailed medical information from another 40 international patients. The male patients never went through puberty and were infertile, consistent with severe GnRH deficiency, whereas the female patients showed signs of partial or full reproductive activity, including normal breast development and menstrual cycles. The authors suggested that females might have unique developmental strategies to safeguard reproduction. Taken together, the results suggested that the olfactory system is not required for proper GnRH neuron development, which contrasts with traditional views. (AAA)
Citation: Delaney A, Volochayev R, Meader B, Lee J, Almpani K, Noukelak GY, Henkind J, Chalmers L, Law JR, Williamson KA, Jacobsen CM, Buitrago TP, Perez O, Cho CH, Kaindl A, Rauch A, Steindl K, Garcia JE, Russell BE, Prasad R, Mondal UK, Reigstad HM, Clements S, Kim S, Inoue K, Arora G, Salnikov KB, DiOrio NP, Prada R, Capri Y, Morioka K, Mizota M, Zechi-Ceide RM, Kokitsu-Nakata NM, Tonello C, Vendramini-Pittoli S, da Silva Dalben G, Balasubramanian R, Dwyer AA, Seminara SB, Crowley WF, Plummer L, Hall JE, Graham JM, Lin AE, Shaw ND. 2020. Insight into the ontogeny of GnRH neurons from patients born without a nose. J Clin Endocrinol 105(5):1538–1551.
(Aidin Alejo Abdala is an Intramural Research Training Award [IRTA] postbaccalaureate fellow in the NIEHS Clinical Investigation of Host Defense Group. Nicholas Alagna is an IRTA fellow in the NIEHS Mechanisms of Mutation Group. Mimi Huang, Ph.D., is an IRTA fellow in the DNTP Systems Toxicology Group. Arif Rahman, Ph.D., is a visiting fellow in the NTP Toxicoinformatics Group. Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)