Extramural papers of the month
By Nancy Lamontagne
- Health implications of temperature variability
- Autism risk linked to maternal diabetes and obesity
- Potential treatment for Parkinson’s disease
- Environmental estrogens and developmental reprogramming
Health implications of temperature variability
Climate change is expected to bring increasing variability in summer temperatures, which could shorten life expectancy for older people with chronic medical conditions, according to a new NIEHS-funded study. Although other studies have looked at the short-term effects of heat waves, this study examined the long-term effects of climate change on life expectancy.
The researchers used Medicare data from 1985 to 2006 to follow the health of 3.7 million chronically ill people over age 65. They studied whether mortality related to variability in summer temperature in 125 cities and took into account other factors, such as winter temperature variance, ozone levels, and individual risk factors. They compiled results for 125 individual cities and then pooled the results.
Within each city, years with larger summer temperature swings showed higher death rates than years with smaller swings. Each 1 degree Celsius increase in summer temperature variability increased the death rate for elderly with chronic conditions between 2.8 and 4.0 percent, depending on the condition. In addition, the researchers found the mortality risk was 1 to 2 percent greater for African Americans and those living in poverty and for African Americans, while the risk was 1 to 2 percent lower for people living in cities with more green space.
Citation: Zanobetti A, O'Neill MS, Gronlund CJ, Schwartz JD. Summer temperature variability and long-term survival among elderly people with chronic disease. Proc Natl Acad Sci U S A 109(17):6608-6613. Story.
Autism risk linked to maternal diabetes and obesity
New findings from the NIEHS-funded Childhood Autism Risks from Genetics and the Environment (CHARGE) study provide evidence that maternal metabolic conditions can increase the risk for autism, as well as developmental delay without autistic symptoms. The study suggests that fetal exposure to elevated levels of glucose and maternal inflammation adversely affect fetal development.
The metabolic conditions studied included obesity or hypertension at the start of pregnancy, or diabetes during pregnancy. Compared to normal-weight mothers without diabetes or hypertension, the researchers found that mothers who were obese were 67 percent more likely to have a child with autism spectrum disorder and more than twice as likely to have a child with another developmental disorder. Mothers with diabetes were also more than twice as likely to have a child with developmental delays as healthy mothers. In addition, children with autism spectrum disorder and diabetic mothers had greater deficits in adaptive communication, language comprehension, and language production than children with autism spectrum disorder born to healthy mothers.
Citation: Krakowiak P, Walker CK, Bremer AA, Baker AS, Ozonoff S, Hansen RL, Hertz-Picciotto I. 2012. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics; doi: 10.1542/peds.2011-2583 [Online 9 April 2012].
Potential treatment for Parkinson’s disease
NIEHS grantees report that the compound CLR01 successfully prevented the aggregation of alpha-synuclein in zebrafish without any toxic effects to healthy brain cells. The protein alpha-synuclein is thought to lead to Parkinson’s disease when it aggregates in the brain and kills neurons, and CLR01 might offer a treatment for slowing or stopping the progression of the disease.
Since alpha-synuclein is found throughout the brain, it is challenging to find a drug that targets only the aggregates without destroying the protein’s normal function. The researchers tested a novel molecular tweezer known as CLR01, which has been shown to inhibit the assembly and toxicity of proteins that have some similarities to alpha-synuclein.
They first experimented with CLR01 in cell cultures, finding that it kept alpha-synuclein from forming aggregates, prevented alpha-synuclein toxicity, and broke up existing aggregates. They also used fluorescent proteins to track CLR01’s effect on the aggregations in a transgenic zebrafish model that expressed human alpha-synuclein in neurons and found that the molecular tweezer prevented alpha-synuclein aggregation and neuronal death.
Citation: Prabhudesai S, Sinha S, Attar A, Kotagiri A, Fitzmaurice AG, Lakshmanan R, Ivanova MI, Loo JA, Klärner FG, Schrader T, Stahl M, Bitan G, Bronstein JM. 2012. A novel "molecular tweezer" inhibitor of alpha-synuclein neurotoxicity in vitro and in vivo. Neurotherapeutics 9(2): 464-476.
Environmental estrogens and developmental reprogramming
An animal study by NIEHS grantees shows that environmental estrogens have distinct epigenetic effects in the developing uterus. The research provides insight into how early-life exposures to environmental estrogens can increase susceptibility to later development of hormone-dependent tumors.
The researchers studied the environmental estrogens genistein and bisphenol A (BPA), finding that genistein promoted the development of uterine fibroids in rats, while BPA did not. In the developing uterus, genistein and BPA both induce estrogen receptor signaling in a genomic manner, so how can they each activate the same receptor system but result in completely different outcomes?
The authors showed that genistein activated membrane-bound estrogen receptor via nongenomic mechanisms that were directly linked to pathways that caused histone phosphorylation. This histone phosphorylation reprograms estrogen-responsive genes in a way that makes them more responsive to hormones and increases the incidence of uterine fibroids later in life. However, BPA bound to the nuclear estrogen receptor without activating the membrane receptor and, therefore, did not activate the nongenomic histone phosphorylation pathway in the neonatal uterus. BPA, therefore, resulted in less estrogen-responsive gene expression in the adult uterus and no increase in uterine fibroids.
Citation: Greathouse KL, Bredfeldt T, Everitt JI, Lin K, Berry T, Kannan K, Mittelstadt ML, Ho SM, Walker CL. 2012. Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. Mol Cancer Res 10(4):546-557.
(Nancy Lamontagne is a science writer with MDB, Inc., a contractor for the NIEHS Division of Extramural Research and Training, Superfund Research Program, and Worker Education and Training Program.)