Epigenetics, microbiome may contribute to Alzheimer’s disease

Epigenetic changes in the brain combined with alterations in the gut microbiome may contribute to Alzheimer’s disease (AD), reported NIEHS grantees. Epigenetic changes turn genes on or off without altering the underlying sequence of DNA. This is the one of the first papers to lay the groundwork for linking brain epigenetics and the gut microbiome.

Researchers explored how different genetic mutations interacted to affect behavior and cognitive function related to AD using two different mouse models of the disease and normal mice. The first model contained two mutations in the human amyloid precursor protein (hAPP), found in human populations, and the second added a third hAPP mutation. APP gene mutations generate protein fragments that accumulate in the brain, called amyloid plaques, and are characteristic of AD.

AD-relevant behaviors and cognitive performance were related to hAPP mutations, gender, and the diversity and composition of the gut microbiome. Microbes in the Lachnospiraceae and Ruminococcaceae families were the most commonly involved in interactions between hAPP mutations and behavior.

In a subset of female mice, the team observed different epigenetic changes related to hAPP mutations and gut microbial makeup. For example, female mice with increased epigenetic changes in a gene known to be involved in AD susceptibility also had greater number of gut microbes in the Lachnospiraceae family.

According to the authors, the microbiome may affect AD-related behaviors and cognitive performance via epigenetic changes in AD-susceptibility genes. However, they were unable to rule out that changes in the epigenome may alter conditions that affect the growth of certain taxa in the gut microbiome.

Citation: Kundu P, Torres ERS, Stagaman K, Kasschau K, Okhovat M, Holden S, Ward S, Nevonen KA, Davis BA, Saito T, Saido TC, Carbone L, Sharpton TJ, Raber J. 2021. Integrated analysis of behavioral, epigenetic, and gut microbiome analyses in AppNL-G-F, AppNL-F, and wild type mice. Sci Rep 11(1):4678.

Prenatal phthalate exposure may affect children’s executive function

Elevated levels of phthalates during pregnancy may negatively affect executive function in children, according to a new NIEHS-funded study. Some changes were especially prominent among boys. Executive function is a set of complex cognitive skills, such as emotional regulation, impulse control, working memory, and attentional flexibility. Executive function enables people to focus, follow directions, and handle emotions, among other things.

Researchers measured 12 phthalate metabolites in urine samples collected at 17 weeks of pregnancy. Among those children sampled, born between 2003 and 2008, the researchers compared 262 children who are affected by attention-deficit hyperactivity disorder symptoms with 78 typically developing children. All children participated in a detailed clinical assessment at 3.5 years, including three performance-based tests and behavior information collected from parents and caregivers.

Exposure to higher levels in maternal urine of mono-benzyl phthalate (MBzP) during the prenatal period was associated with poorer executive function in both sexes. Specifically, MBzP was associated with effects on working memory, emotional control, and inhibition as rated by parents and teachers and evaluated in administered tests.

Affected executive function was also related to higher levels of mono-n-butyl phthalate and mono-iso-butyl phthalate, although results varied by evaluation method. For example, inhibition reported by parents was most affected by both chemicals, with stronger associations among boys. However, no differences were found between girls and boys when considering inhibition rated by teachers or by the three performance tests.

According to the researchers, the prenatal period may represent a critical window of exposure where phthalates may harm later executive functioning, particularly for boys.

Citation: Choi G, Villanger GD, Drover SSM, Sakhi AK, Thomsen C, Nethery RC, Zeiner P, Knudsen GP, Reichborn-Kjennerud T, Overgaard KR, Herring AH, Skogan AH, Biele G, Aase H, Engel SM. 2021. Prenatal phthalate exposures and executive function in preschool children. Environ Int 149:106403.

Hospitalization following extreme weather, opportunities for resilience

NIEHS-funded researchers observed an increase in respiratory disease and other hospitalizations among older adults following exposure to tropical cyclones, which may help hospitals become better prepared in the future. Tropical cyclone is a generic term used to describe tropical depressions, tropical storms, and hurricanes.

The team used data on 70 million Medicare hospitalizations for individuals 65 years and older and a comprehensive database of county-level local winds to estimate tropical cyclone exposures between 1999 and 2014. Using advanced statistical models, they examined how tropical cyclone exposure related to hospitalizations for 13 different causes.

In the week following tropical cyclone exposure, researchers observed an average increase in hospitalizations from several causes, including respiratory diseases, infectious and parasitic diseases, and injuries. The most pronounced increase was for respiratory diseases, with a 14% average increase in hospitalizations, including a peak 30% increase one day after exposure. Hospitalizations from chronic obstructive pulmonary disease were 45% higher in the week following tropical cyclone exposure. While hospitalizations for chronic conditions, like cancer, and nonemergency hospitalizations declined, the team estimated nearly 17,000 additional hospitalizations overall.

According to the researchers, results demonstrate the need for targeted hospital preparedness strategies before, during, and after tropical cyclones and other extreme weather. For example, hospitals could plan for shelters to provide electricity and common medications, or to quickly prioritize strategies for vulnerable people with certain chronic conditions to find and use resources outside of hospitals.

Citation: Parks RM, Anderson GB, Nethery RC, Navas-Acien A, Dominici F, Kioumourtzoglou MA. 2021. Tropical cyclone exposure is associated with increased hospitalization rates in older adults. Nat Commun 12(1):1545.

Tungsten linked with chronic kidney disease

Exposure to tungsten may decrease the time it takes to develop to chronic kidney disease (CKD), and may be associated with CKD of unknown origin (CKDu), according to a new NIEHS-funded study. CKD is a public health problem around the world, particularly in agricultural communities. The San Luis Valley is a rural agricultural community in southern Colorado with several risk factors for CKD, including a water supply contaminated by heavy metals.

Researchers compiled existing data on metals in urine of 1,659 people in the San Luis Valley, along with social, demographic, and clinical information. Using advanced statistical approaches, the scientists looked for associations between tungsten concentration in urine and the time to develop CKD. In a subset of individuals, they also evaluated the relationship between tungsten and biological markers of kidney injury and CKDu.

Urine tungsten was strongly associated with decreased time-to-CKD, even after controlling for high blood pressure and diabetes, known risk factors for CKD. For example, every doubling of tungsten in urine was associated with up to 31% higher odds of developing the disease within 5 years. Urinary tungsten in the 95th percentile of exposure was also associated with CKDu after adjusting for known CKD risk factors. One biological marker of kidney injury was significantly elevated with higher tungsten in urine in individuals without diabetes.

According to the researchers, tungsten warrants further study as a potential risk factor for CKD and a contributor to CKDu, which may act by directly harming the kidneys.

Citation: Fox J, Macaluso F, Moore C, Mesenbring E, Johnson RJ, Hamman RF, James KA. 2021. Urine tungsten and chronic kidney disease in rural Colorado. Environ Res 195:110710.