Papers of the Month
By Sara Mishamandani
Genetic changes in uterus linked to fetal BPA exposure in mice
Exposure to low levels of bisphenol A (BPA) during fetal development permanently altered the uterine genome in mice, according to a new study by NIEHS-funded researchers. The changes they found mainly affected genes implicated in estrogen-related diseases, such as infertility, endometriosis, osteoporosis, prostate cancer, obesity, and breast cancer.
Researchers exposed pregnant mice to low levels of BPA and compared the genetic and epigenetic profiles in the uterus of offspring to the profiles of unexposed mice. They also examined how genes in the uterus responded to estrogen during and after sexual maturity. They discovered changes in the estrogen responses of almost 1,000 genes in the BPA-exposed mice. Some of the changes only became apparent after sexual maturity and were not seen at birth or in early life.
With conflicting reports on the health effects of low levels of BPA, this study confirms that BPA is an active compound and can negatively impact fetal development. According to the authors, the findings demonstrate that BPA leads to a detrimental change in uterine response to estrogens, and steps should be taken to reduce maternal exposure to BPA during pregnancy.
Jorgensen EM, Alderman MH 3rd, Taylor HS. 2016. Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol-A) exposure. FASEB J; doi:10.1096/fj.201500089Rfj.201500089R [Online 16 June 2016].
Protecting against pesticide-linked Parkinson's disease
A new study by NIEHS-funded researchers uncovered information linking a common group of pesticides with Parkinson’s disease and revealed how a drug may protect against the chemical-induced pathway to the disease. Using zebrafish, they found that getting rid of the protein alpha-synuclein, a potential target for therapeutics, protected against toxicity of the pesticide ziram. Ziram is used extensively in agriculture, and has been previously linked to an increased risk of developing Parkinson’s disease, but the mechanism was not clearly understood.
In the study, researchers began by exposing zebrafish to ziram and found that it led to loss of dopaminergic neurons, the main source of dopamine to the central nervous system, and abnormal swimming behavior — both signs of a Parkinson’s-like condition. To determine if alpha-synuclein proteins contributed to the changes, the researchers genetically eliminated the alpha-synuclein proteins and observed that these zebrafish were protected from the signs of a Parkinson’s-like condition. They also discovered that the investigational drug CLR01, which is being developed to break up protein aggregates in Parkinson’s patients, provided protection from the Parkinson’s-like condition in normal zebrafish.
The scientists found that either getting rid of the alpha-synuclein protein or breaking up its aggregates protect the zebrafish against ziram toxicity. These findings could potentially extend to other chemicals that may induce Parkinson’s disease, a disease in which more than 70 percent of cases cannot be explained by genetics.
Lulla A, Barnhill L, Bitan G, Ivanova MI, Nguyen B, O'Donnell K, Stahl MC, Yamashiro C, Klarner FG, Schrader T, Sagasti A, Bronstein JM. 2016. Neurotoxicity of the Parkinson's disease-associated pesticide ziram is synuclein-dependent in zebrafish embryos. Environ Health Perspect; doi:10.1289/ehp141 [Online 15 June 2016].
Reducing GI illnesses by extending municipal water service
NIEHS-funded researchers provided new evidence that extending regulated community water service to households currently relying on private wells may decrease the burden of acute gastrointestinal (GI) illness. By combining data on visits to the emergency department for acute GI illness with water quality data, the researchers linked microbial contamination of drinking water from private wells to cases of acute GI illness in North Carolina.
The researchers used 2007-2013 data from North Carolina emergency departments, along with data from community water systems and more than 16,000 water samples from private wells in North Carolina. Approximately 35 percent of the population of North Carolina depends on private wells. The scientists found that 29,400 visits to emergency departments, or 7.3 percent of all emergency visits for acute GI illness, were associated with microbial contamination of drinking water. Of these cases, 99 percent were associated with private well contamination.
The study estimated that the annual cost of emergency department visits attributable to microbes in private wells is $39.9 million in North Carolina. As a result, the authors suggested that extending municipal water service into areas with higher population density that are close to existing infrastructure, while factoring in the potential health benefits, may make municipal service expansion economically feasible. The authors also estimated that extending community water service to just 10 percent of the population currently using private wells in North Carolina could prevent 2,920 annual emergency department visits for acute GI illness.
DeFelice NB, Johnston JE, Gibson JM. 2016. Reducing emergency department visits for acute gastrointestinal illnesses in North Carolina (USA) by extending community water service. Environ Health Perspect; doi:10.1289/ehp160. [Online 20 May 2016].
Possible new marker and therapeutic target for liver cancer
High levels of the protein p62 in human liver samples are associated with cancer recurrence and reduced patient survival, according to a new study by NIEHS-funded researchers. The researchers also found that p62, a protein known to recognize cellular waste that needs to be degraded, is required to induce liver cancer in mice.
The research team looked at noncancerous liver samples from people who previously underwent treatment to destroy liver cancer. They found that people with high levels of p62 were more likely to see their cancer return and less likely to survive cancer-free than people with low or no p62. They then investigated the protein in mice and discovered that p62 activated other proteins and genes that help stressed cells survive, allowing the cells to live longer and accumulate cancer-causing mutations, ultimately forming tumors. Because liver tumors could not form without the protein, study authors suggested that molecules interfering with p62 may be useful for preventing the progression of chronic liver disease to liver cancer.
The protein p62 is known to be elevated in many different cancers, including in the liver, but its role in cancer has not been clearly understood. This study shows that p62 is necessary to induce liver cancer in mice and is associated with cancer recurrence in humans, suggesting that it could be used to predict the course of the disease and as a potential therapeutic target for liver cancer.
Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S, Font-Burgada J, Zhong Z, Subramaniam S, Raghunandan S, Duran A, Linares JF, Reina-Campos M, Umemura S, Valasek MA, Seki E, Yamaguchi K, Koike K, Itoh Y, Diaz-Meco MT, Moscat J, Karin M. 2016. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29(6):935-948.