Sunday, June 11, 2017

Researcher discovers link between toxicants and lipid metabolism

A recent study has uncovered the link between toxicants and lipid metabolism.

While working for an environmental nonprofit organization, a researcher  investigated how poor waste management and sanitation practices can impact the environment and public health. Her work sparked an interest in environmental toxicology and led her as a doctoral student in the field. She spent her time in graduate school using Daphnia magna, or water fleas, as model organisms for studying environmental health. She started investigating how these organisms respond to different environmental toxicants.


The culmination of her research indicates that certain toxicants can disrupt the maturation of Daphnia by altering the level of lipids (fats, waxes and their relatives) present in the species. These findings take a step toward understanding how a specific pathway - one of sphingomyelin metabolism - affects development.
Sphingomyelin, the key lipid of the study, was first noticed by Sengupta and colleagues because it isn't present in embryonic or in adult Daphnia, but rather in newborns, indicating it plays a significant role in development and progression to reproductive maturity.

"That's actually one of the coolest findings, not even toxicology-related, but a basic biochemical finding," said and co-author. "Sphingomyelin is very important in the maturation of this species." This age-specific presence of sphingomyelin is supported by previously published data that implicated sphingomyelin and the alcohol it breaks into, sphingosine, in the reproduction and development in fruit flies, roundworms and mice.

To uncover this role in Daphnia, Sengupta and colleagues first honed in on the HR96 receptor found in cell nuclei that is responsible for a variety of functions, such as sensing foreign chemicals in the body and regulating genes involved in energy metabolism and lipid distribution. They then exposed adult Daphnia to toxicants and fatty acids that either jump-started or inhibited the function of HR96.

When exposed to atrazine, one of the most commonly used herbicides, HR96 activity was activated. Exposure to triclosan, an antibacterial agent found in personal care products, inhibited HR96 activity. The adult Daphnia were then deprived of nutrition to investigate their ability to reproduce or survive under stress conditions. The nutritional-control aspect of the study's design was one variable that separated it from prior studies in Daphnia.

"In toxicology, when you do these tests, you always do them under ideal conditions, but that's not what really happens in the environment. Sometimes there's plenty of food, and sometimes there's not," said a researcher. "All of a sudden, triclosan, which looks like it doesn't have much of an effect, might actually have affects depending on the time of year and the food that's available. This indicates interplay between the natural environment and the toxicant that we don't look at in the laboratory very often."

When stressed with lack of food, the Daphnia showed a number of effects, depending on what toxicant or fatty acid they were treated with. Exposure to triclosan increased the level of lipids in the adult Daphnia, more so than any other treatment, but this resulted in a struggle to reproduce. If triclosan-treated adults did bear offspring, their newborns had very low levels of lipids present, indicating that lipids are not being allocated properly in newborn Daphnia. However, triclosan-newborns saw an increase in the level of sphingomyelin present, again clueing the researchers into sphingomyelin's role in maturation. The triclosan-newborns also exhibited stunted growth and development, though they did survive for a long period of time.

This result might incite a correlation between high sphingomyelin levels and stunted growth, but Baldwin was quick to point out that this isn't necessarily the case. Docosahexaenoic acid (DHA), an omega-3 fatty acid found in fish, was supplemented to a separate group of nutritionally deprived Daphnia. Like triclosan, DHA is an inhibitor of HR96 activity, though it is naturally occurring in the environment.

Atrazine, the toxicant HR96 activator in the study, was the only treatment that affected reproduction rates under normal conditions. What was poor reproduction before depriving the Daphnia of nutrition was only heightened by forcing them into a starved state. Atrazine-treated Daphnia also bore newborn with decreased levels of sphingomyelin. These results, combined with those of triclosan, suggest that commonly used toxicants can severely alter the allocation of fats in Daphnia magna, thereby causing a disruption in their maturation process. Such a conclusion was further confirmed after the researcher and colleagues found that most HR96 genes involved in sphingomyelin metabolism were disrupted after toxicant exposure.

The study is published in a medical journal.

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Wednesday, May 04, 2016

Reasons for inflammation in diabetic kidney disease revealed

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 A team of researchers have identified key inflammatory mechanisms underlying Type 1 diabetes and obesity-related kidney dysfunction.
Diabetic kidney disease is the leading cause of end-stage kidney disease and is a major risk factor for cardiovascular disease.

The findings showed that an increase in amounts of Sphingomyelin -- a type of fatty acid commonly found in cell membranes and nervous tissue -- has the potential to trigger the inflammatory mechanisms that can damage functioning of kidneys.

Sphingomyelin has been known to drive an increase in the ratio of adenosine triphosphate (ATP) and adenosine monophosphate (AMP) -- molecules involved in intracellular energy transfer in kidneys -- in glomerular cells of the kidney in mice with diabetes, obesity or both.

Diabetes and obesity leads to an increase in the ATP levels and decreases the AMP levels, disrupting the balance leading to the dysfunctioning of the kidneys.

"We believe that sphingomyelin fuels increases in ATP and decreases in AMP that result in inflammation which leads to cell dysfunction, fibrosis and endothelial damage underlying diabetic kidney disease," said Sharma, professor at the University of California San Diego in the US.


 The team analysed the kidneys of experimental mice with Type 1 diabetes and mice fed on a high-fat diet.
The results also showed that deficiency in the production of insulin in the body or the resistance to externally induced insulin leads to an increase in amounts of sphingomyelin.

"We found that insulin deficiency and insulin resistance, two hallmarks of diabetes, seem to be associated with increased sphingomyelin in the kidney, which trigger damaging inflammatory mechanisms," Sharma noted in the paper published online in the journal EbioMedicine.

The insights could have major impact on developing new biomarkers and novel therapeutics for diabetic and obesity-related kidney diseases.

"It may be possible to create new treatments by blocking ATP and the inflammatory pathways consequent to that or by developing ways to reduce the amount or activity of sphingomyelin in the kidney," Sharma concluded.

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