Health Research Report
146th Issue Date 11 JAN 2013
Compiled By Ralph Turchiano
In this issue:
1. Foodborne Illness Could Have Sinister Causes : Medications being intentionally added
2. Cholesterol medicine affects energy production in muscles
3. Sublingual immunotherapy shows promise as treatment for peanut allergy
4. Hold the diet soda? Sweetened drinks linked to depression, coffee tied to lower risk
5. Disappearing bacterium may protect against stroke
6. High fiber diet prevents prostate cancer progression
7. High Fructose Corn Syrup Direct Correlation with Autism in the U.S. – Clin Epigenetics. 2012 (Excerpt)
Foodborne Illness Could Have Sinister Causes : Medications being intentionally added
Observation Article: Foodborne Illness Could Have Sinister Causes
Doctors should consider the intentional addition of medicine to food as a potential cause of foodborne disease outbreaks. The World Health Organization suggests possible sources of foodborne disease outbreaks are pathogenic bacteria, viruses, protozoa, parasitic worms, natural toxins, and chemicals, but not medicines. A 2010 foodborne disease outbreak in Beijing, China was a result of clonidine, a medication used to treat hypertension and ADHD, being intentionally added to lunch ingredients. Eighty travelers who had just finished lunch in a Beijing restaurant began to feel faint. Within a few hours they developed dizziness, weakness, lethargy, dry mouth, and nausea, among other troublesome symptoms. At a nearby hospital, the travelers were treated for low blood pressure and low heart rate. With no response to treatment, the patients were referred for a screening for common toxins and drugs. The screening found clonidine in the patients’ systems. The patients were treated for clonidine poisoning and symptoms resolved in all patients within 48 hours. After six days, all patients had been discharged from the hospital and at one year no patients had residual symptoms. An investigation found that two persons put clonidine into the starch used to make certain dishes (the kitchen staff would not notice the addition because starch and clonidine are both white, odorless powders) to gain a competitive advantage for a nearby restaurant.
Cholesterol medicine affects energy production in muscles
Painful side effects
Up to 75 per cent of patients who take statins to treat elevated cholesterol levels may suffer from muscle pain. Scientists at the Center for Healthy Aging at the University of Copenhagen have now identified a possible mechanism underlying this unfortunate side effect. The results have just been published in the well-reputed Journal of American College of Cardiology.
Statin is a class of drugs which are used to treat high levels of blood cholesterol by way of inhibiting the liver’s ability to produce cholesterol. Statins are the most potent drugs on the market for lowering low-density cholesterol (LDL). At present 600,000 Danes with elevated cholesterol levels take statins daily. 30-40 per cent of the older Danish population (ages 65+) are currently undergoing treatment.
From 30-40% of the older Danish population (ages 65+) are currently undergoing treatment with statins.
“A well-known side effect of statin therapy is muscle pain. Up to 75 per cent of the physically active patients undergoing treatment for high cholesterol experience pain. This may keep people away from either taking their medicine or from taking exercise – both of which are bad choices,” says Professor Flemming Dela from the Center for Healthy Aging at the University of Copenhagen. He continues:
“We have now shown that statin treatment affects the energy production in muscles. We are working on the assumption that this can be the direct cause of muscle weakness and pain in thepatients.”
Scientists also showed that the patients examined who were being treated with statins had low levels of the key protein Q10. Q10 depletion and ensuing lower energy production in the muscles could be the biological cause of the muscle pain that is a problem for many patients.
Side effects of statin therapy
About 40 per cent of the patients being treated with statins in Denmark are in so-called ’mono therapy’ and thus are prescribed only this one drug. Presumably these are people who ‘only’ have high cholesterol and no other risk factors that could influence heart health:
“The effect of statins is marginal for these patients – in a previous published Cochrane analysis only 0.5% reduction in all-cause mortality was detected, indicating that for every 200 patients taking statins daily for five years, one death would be prevented. This patient group is obviously interesting in light of the side effects of statin therapy,” comments Professor Flemming Dela.
The media influence patients
“The new study is the basis for a large planned research project, where we will focus broadly on patients undergoing statin treatment. We will look at statin consumption from a medical point of view, and will also investigate the media’s influence on patients’ acceptance or rejection of statins as a treatment option. Many contradictory views find their way into the public forum, and it can be difficult for patients to distinguish between fact and fiction,” continues Professor Flemming Dela.
Scientists will also be looking at how home-monitoring of cholesterol levels influences patients – for example, does it make patients feel more or less secure when they take responsibility for their own health in this manner? The Center for Healthy Aging is currently seeking funding for the research project.
Professor Flemming Dela
Phone: +45 35 32 74 25
Sublingual immunotherapy shows promise as treatment for peanut allergy
CHAPEL HILL, N.C. – Peanuts are one of the most common triggers of severe food-induced allergic reactions, which can be fatal, and the prevalence of peanut allergy is increasing. However, there is currently no clinical treatment available for peanut allergy other than strict dietary elimination and, in cases of accidental ingestion, injections of epinephrine.
But a new multicenter clinical trial shows promise for sublingual immunotherapy (SLIT), a treatment in which patients are given daily doses, in gradually increasing amounts, of a liquid containing peanut powder. The patients first hold the liquid under the tongue for 2 minutes and then swallow it.
The two lead authors of the study, published in the January 2013 issue of the Journal of Allergy and Clinical Immunology, are David M. Fleischer, MD, of National Jewish Health in Denver, Colo., and Wesley Burks, MD, Curnen Distinguished Professor and Chair of the Department of Pediatrics in the University of North Carolina School of Medicine.
“These results are encouraging,” Burks said. “The immune response was stronger than we thought it might be, and the side effects of this treatment were relatively small. However, the magnitude of the therapeutic effect was somewhat less than we had anticipated. That’s an issue we plan to address in future studies.”
In the study, 40 people with peanut allergy, ages 12 to 37 years, were randomized to receive daily peanut or placebo SLIT. All were given a baseline oral food challenge of up to 2 grams of peanut powder to test how much peanut powder they could consume without symptoms.
After 44 weeks, all were given a second oral food challenge. Those who were able to consume either 5 grams, or at least 10-fold more peanut powder than their baseline amount, were considered to be responders (i.e., desensitized to peanut). At 44 weeks, 70 percent of those who received peanut SLIT were responders, compared to 15 percent of those receiving placebo. Among the peanut-SLIT responders, the median amount of peanut powder they could successfully consume increased from 3.5 to 496 milligrams. After 68 weeks, that amount increased significantly, to 996 milligrams.
Of 10,855 peanut doses given through week 44 of the study, 63.1 percent were symptom-free. When oral/pharyngeal symptoms were excluded from the analysis, 95.2 percent of doses were symptom-free.
The study concluded that peanut SLIT safely induced desensitization in a majority of participants compared to placebo, and that longer duration of therapy led to significant increases in the amount of peanut powder people could safely consume.
However, Burks cautions, this is not a treatment that people should try on their own. For now it’s a treatment that should only be given by medical professionals in a carefully monitored clinical trial, he said.
Study participants were recruited from five U.S. sites: New York, N.Y.; Baltimore, Md.; Little Rock, Ark.; Denver, Colo.; and Durham, N.C. Study co-authors include researchers from the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Johns Hopkins University School of Medicine, Mount Sinai School of Medicine, the EMMES Corp. in Rockville, Md., and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH).
The study was funded by grants from the NIAID and the NIH’s National Center for Research Resources.
Hold the diet soda? Sweetened drinks linked to depression, coffee tied to lower risk
SAN DIEGO – New research suggests that drinking sweetened beverages, especially diet drinks, is associated with an increased risk of depression in adults while drinking coffee was tied to a slightly lower risk. The study was released today and will be presented at the American Academy of Neurology’s 65th Annual Meeting in San Diego, March 16 to 23, 2013.
“Sweetened beverages, coffee and tea are commonly consumed worldwide and have important physical—and may have important mental—health consequences,” said study author Honglei Chen, MD, PhD, with the National Institutes of Health in Research Triangle Park in North Carolina and a member of the American Academy of Neurology.
The study involved 263,925 people between the ages of 50 and 71 at enrollment. From 1995 to 1996, consumption of drinks such as soda, tea, fruit punch and coffee was evaluated. About 10 years later, researchers asked the participants whether they had been diagnosed with depression since the year 2000. A total of 11,311 depression diagnoses were made.
People who drank more than four cans or cups per day of soda were 30 percent more likely to develop depression than those who drank no soda. Those who drank four cans of fruit punch per day were about 38 percent more likely to develop depression than those who did not drink sweetened drinks. People who drank four cups of coffee per day were about 10 percent less likely to develop depression than those who drank no coffee. The risk appeared to be greater for people who drank diet than regular soda, diet than regular fruit punches and for diet than regular iced tea.
“Our research suggests that cutting out or down on sweetened diet drinks or replacing them with unsweetened coffee may naturally help lower your depression risk,” said Chen. “More research is needed to confirm these findings, and people with depression should continue to take depression medications prescribed by their doctors.”
The study was supported by the National Institutes of Health, the National Institute of Environmental Health Sciences and the National Cancer Institute.
Learn more about depression, which commonly affects people with brain diseases, at http://www.aan.com/patients.
The American Academy of Neurology, an association of more than 25,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, brain injury, Parkinson’s disease and epilepsy.
For more information about the American Academy of Neurology, visit http://www.aan.com or find us on Facebook, Twitter, Google+ and YouTube.
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Disappearing bacterium may protect against stroke
H. pylori isn’t a major cause of death and may protect against stroke and some cancers
New York (January 9, 2013) — A new study by NYU School of Medicine researchers reveals that an especially virulent strain of the gut bacterium Helicobacter pylori (H. pylori) isn’t implicated in the overall death rate of the U.S. population, and may even protect against stroke and some cancers. The findings, based a nationwide health survey of nearly 10,000 individuals over a period of some 12 years, are published online, January 9, in the journal Gut.
Those individuals carrying the most virulent strain of H. pylori, the study found, had a 55 percent reduced risk of deaths from stroke compared with their counterparts who were not infected with H. pylori. Participants with the most virulent strain also had a 45 percent reduced risk of death from lung cancer.
These surprising findings emerged from an analysis by Yu Chen, PhD, MPH, associate professor of population health and environmental medicine, and Martin J. Blaser, MD, professor of internal medicine and professor of microbiology, of individuals who participated in a national survey designed to assess the health and nutritional status of adults and children in the United States. Previous studies by Dr. Blaser have confirmed the bacterium’s link to gastric diseases ranging from gastritis to stomach cancer. He and Dr. Chen have more recently shown that H. pylori may protect against childhood asthma. The most virulent H. pylori strains have a gene called cagA.
“The significance of this study is that this is a prospective cohort of participants representative of the U.S. population with a long follow-up,” says Dr. Chen. “We studied both the overall H. pylori as well as cagA strain of H. pylori, which is more interactive with the human body. We found that H. pylori is not related to the risk of death from all causes, despite it being related to increased risk of death from gastric cancer.”
“This finding confirms earlier work, however, that gastric cancers are now uncommon in the United States,” says Dr. Chen. “We also found that H. pylori was related to a reduced risk of stroke and lung cancer, and these effects were stronger for the cagA strain, suggesting its mixed role in human health,” she says.
H. pylori, an ancient bacterium, lives in the mucous layer lining the stomach where, until recently, it survived for decades. More than half of the world’s population harbor H. pylori in their upper gastrointestinal tract. Mainly transmitted in families, the bacterium is usually acquired before age 10. In developing countries H. pylori is still prevalent, but is vanishing in the developed world thanks to better sanitation and widespread use of antibiotics.
To better understand the relationship between H. pylori and the overall death rate, or all-cause mortality, the researchers analyzed data from 9,895 participants in the National Health and Nutrition Surveys (NHANES III), enrolled from 1988 to 1994. Test results for H. pylori and cagA were available on 7,384 subjects at the time of enrollment, and participants were followed until 2000.
There was no association of either H. pylori-positivity or cagA-positivity with all-cause mortality in the population, the researchers found. Participants with and without H. pylori experienced a similar risk of death from all causes. Consistent with past reports, a strong association was observed between H. pylori and gastric cancer mortality, according to the study. Individuals who were H. pylori positive were 40 times more likely to die from gastric cancer. The study also found that participants with cagA-positivity had a 55 percent reduced risk of deaths from stroke compared with their counterparts who were H. pylori negative/ cagA-negative. Participants with cagA-positivity also had a 45 percent reduced risk of deaths from lung cancer.
“The most interesting finding was that there is a strong inverse association with stroke which could be protective,” says Dr. Blaser. “There is some precedent for this and it is possible that the same cells (T reg cells) that H. pylori induces that protect against childhood asthma could be the protective agents, however, the findings need to be confirmed.”
Authors: Yu Chen. PhD, MPH, associate professor, Departments of Population Health and Environmental Medicine; Stephanie Segers, MPH, statistician, Department of Population Health; Martin J. Blaser, MD, professor, Departments of Medicine and Microbiology.
Competing Interests: None reported.
Funding/Support: This work was supported in part by grants R01DK090989, R01GM63270, ES000260, and P30CA16087 from the National Institutes of Health, and by the Diane Belfer Program for Human Microbial Ecology.
About NYU School of Medicine:
NYU Langone Medical Center, a world-class, patient-centered, integrated, academic medical center, is one on the nation’s premier centers for excellence in clinical care, biomedical research and medical education. Located in the heart of Manhattan, NYU Langone is composed of three hospitals – Tisch Hospital, its flagship acute care facility; the Rusk Institute of Rehabilitation Medicine, the world’s first university-affiliated facility devoted entirely to rehabilitation medicine; and the Hospital for Joint Diseases, one of only five hospitals in the nation dedicated to orthopaedics and rheumatology – plus the NYU School of Medicine, which since 1841 has trained thousands of physicians and scientists who have helped to shape the course of medical history. The medical center’s tri-fold mission to serve, teach and discover is achieved 365 days a year through the seamless integration of a culture devoted to excellence in patient care, education and research.
High fiber diet prevents prostate cancer progression
Komal Raina, PhD, shows that prostate cancers in mice fed a high-fiber diet fail to progress.
A high-fiber diet may have the clinical potential to control the progression of prostate cancer in patients diagnosed in early stages of the disease.
The rate of prostate cancer occurrence in Asian cultures is similar to the rate in Western cultures, but in the West, prostate cancer tends to progress, whereas in Asian cultures it does not. Why? A University of Colorado Cancer Center study published in the January 2013 issue of the journal Cancer Prevention Research shows that the answer may be a high-fiber diet.
The study compared mice fed with of inositol hexaphosphate (IP6), a major component of high-fiber diets, to control mice that were not. Then the study used MRI to monitor the progression of prostate cancer in these models.
“The study’s results were really rather profound. We saw dramatically reduced tumor volumes, primarily due to the anti-angiogenic effects of IP6,” says Komal Raina, PhD, research instructor at the Skaggs School of Pharmacy and Pharmaceutical Sciences, working in the lab of CU Cancer Center investigator and School of Pharmacy faculty member, Rajesh Agarwal, PhD.
Basically, feeding with the active ingredient of a high-fiber diet kept prostate tumors from making the new blood vessels they needed to supply themselves with energy. Without this energy, prostate cancer couldn’t grow. Likewise, treatment with IP6 slowed the rate at which prostate cancers metabolized glucose.
Possible mechanisms for the effect of IP6 against metabolism include a reduction in a protein called GLUT-4, which is instrumental in transporting glucose.
“Researchers have long been looking for genetic variations between Asian and Western peoples that could explain the difference in prostate cancer progression rates, but now it seems as if the difference may not be genetic but dietary. Asian cultures get IP6 whereas Western cultures generally do not,” Raina says.
The research provides the cover image of this month’s issue of the journal.
Support provided in part by NCI RO1grant CA116636, the NCI Cancer Center P30 CA046934, and the NCRR CTSA UL1 RR025780
Herbal treatments for postmenopausal symptoms can be recommended as an alternative to HRT
Herbal and complementary medicines could be recommended as an alternative to hormone replacement therapy (HRT) for treating postmenopausal symptoms says a new review published today in The Obstetrician and Gynaecologist (TOG).
The review outlines the advantages and limitations of both pharmacological and herbal and complementary treatments for women with postmenopausal symptoms.
The menopause is defined as the time after a woman’s menstrual periods have ceased (12 months after a woman’s final menstrual period). It is associated with an estrogen deficiency and can cause an increase in vasomotor symptoms (hot flushes), genitourinary symptoms (vaginal dryness, sexual dysfunction, frequent urinary tract infections, urinary incontinence), and musculoskeletal symptoms (joint pain) as well as sleep and mood disturbance.
One of the most common menopausal symptoms is hot flushes; approximately two-thirds of postmenopausal women will experience them, and 20% of women can experience them for up to 15 years, states the review.
Estrogen deficiency can also lead to longer-term health issues such as cardiovascular disease and osteoporosis. While pharmacological agents are available to treat postmenopausal symptoms, many non-pharmacological treatment options are also available.
HRT is the most effective treatment of hot flushes, improving symptoms in 80 – 90% of women, says the review. However, the author notes that there are possible health risks associated with HRT, such as links to breast cancer, blood clots, stroke, and cardiovascular problems.
Due to these possible risks, other treatment options may be equally effective, such as behaviour modification and herbal and complimentary medicines, says the author.
The review states that as many as 50 – 75% of postmenopausal women use herbal options to treat hot flushes, and of the complimentary therapies, soy, red clover and black cohosh have been the most investigated.
Soy is the most common plant containing estrogen, found naturally in food and supplements. Previous research has shown a reduction in hot flush symptoms with soy ranging from 20 – 55%. Red clover, a legume also containing estrogen, and black cohosh, a plant originating from the eastern United States and Canada, have also been reported to ease postmenopausal symptoms.
The author of the review recommends these herbal treatments as there are no significant adverse side effects associated with them, as long as they are used in women who do not have a personal history of breast cancer, are not at high risk for breast cancer, and are not taking tamoxifen. However, the review notes that herbal medicines are not regulated in many countries, and therefore the contents of a given product may vary from sample to sample.
Iris Tong, Director of Women’s Primary Care at the Women’s Medicine Collaborative, The Warren Alpert Medical School of Brown University, Rhode Island, and author of the review said:
“Up to 75% of women use herbal and complimentary medicines to treat their postmenopausal symptoms. Therefore, it is vitally important for healthcare providers to be aware of and informed about the non-pharmacological therapies available for women who are experiencing postmenopausal symptoms and who are looking for an alternative to HRT.”
TOG‘s Editor –in-Chief, Jason Waugh said:
“Postmenopausal symptoms can be very distressing and it is important to review the advantages and limitations of the non-pharmacological treatments available as well as the pharmacological ones. Even simple behaviour modification can make a difference to postmenopausal symptoms, including keeping the room temperature cool, wearing layered clothing, relaxation techniques and smoking cessation.”
High Fructose Corn Syrup Direct Correlation with Autism in the U.S. – Clin Epigenetics. 2012 (Excerpt)
EEV: Highlights Although there are many potential causes. We chose to highlight HFCS, due to its toxin amplification.
1) Ca, Mg and Zn, or losses or displacement of any of these minerals from the consumption of HFCS
2) mercury (Hg) and fructose may both modulate PON1 activity
3) mercury (Hg) that may occur from the low Hg concentrations sometimes found in HFCS as a result of the manufacturing process
4) HFCS, may further enhance the toxic effects of lead (Pb) on cognitive and behavioral development in children
Initial Study date: 10 APR 2012
A macroepigenetic approach to identify factors responsible for the autism epidemic in the United States
The number of children ages 6 to 21 in the United States receiving special education services under the autism disability category increased 91% between 2005 to 2010 while the number of children receiving special education services overall declined by 5%. The demand for special education services continues to rise in disability categories associated with pervasive developmental disorders. Neurodevelopment can be adversely impacted when gene expression is altered by dietary transcription factors, such as zinc insufficiency or deficiency, or by exposure to toxic substances found in our environment, such as mercury or organophosphate pesticides. Gene expression patterns differ geographically between populations and within populations. Gene variants of paraoxonase-1 are associated with autism in North America, but not in Italy, indicating regional specificity in gene-environment interactions. In the current review, we utilize a novel macroepigenetic approach to compare variations in diet and toxic substance exposure between these two geographical populations to determine the likely factors responsible for the autism epidemic in the United States.
A macroepigenetic model to explain gene-environment interactions in autism
In public health, epidemiology arguably has led the way in researching gene-environment interactions by studying how genotypes, environmental exposures and disorder outcomes occur in the human population . However, this epidemiological approach has often resulted in contradictory scientific conclusions when its practitioners do not consider the dietary factors that interact and modulate the molecular and genetic mechanisms underlying human metabolism and brain function . This has been the case despite the existence of literature from the field of “nutrigenomics”, which has specifically studied the effects of food and food ingredients on gene expression. In identifying the public health and the social and/or environmental determinants of disease, it seems invalid to study epidemiology without nutrigenomics, or vice versa. In other words, a more macro-level approach to unraveling the full range of environmental and genetic factors contributing to these kinds of neurological disorders ought to include nutrition factors as a component of the environment. By combining information derived from both nutrigenomic and epidemiology studies, a macroepigenetic model has already been developed to explain some of the gene-environment interactions with dietary factors that lead to the development of autism and ADHD .
Figure 1 shows the Mercury Toxicity model that provides a macroepigenetic explanation of how human neurodevelopment can be adversely impacted when gene expression is altered by dietary transcription factors such as zinc insufficiency or deficiency, or by exposure to toxic substances found in our environment, such as the heavy metals mercury and copper . Elimination of heavy metals requires the expression of the metallothionein (MT) gene, which synthesizes the Zn-dependent metal binding protein metallothionein . With dietary zinc (Zn) loss and copper (Cu) gain from the consumption of high fructose corn syrup (HFCS) , metabolic processes required to eliminate heavy metals are impaired in children with autism . Mercury has been found in samples of high fructose corn syrup and is allowable in trace amounts in certain food colors so long as the concentration does not exceed one part per million [17,18]. Mercury (Hg) and specific other heavy metals, including lead (Pb), copper (Cu), cadmium (Cd), silver (Ag) and bismuth (Bi), are capable of displacing the Zn atom in the MT protein molecule . This ‘pathogenic’ displacement of Zn impairs the MT molecule and its ability to pick up the heavy metal and carry it out of the body. If the diet is deficient in Zn or the absorption of Zn is impaired, then the body may not produce enough MT protein to carry and excrete the heavy metal load [19,20]. Children with autism may be Zn deficient and often have MT dysfunction [21–23]. Because of their diminished capacity to excrete toxic heavy metals, the severity of their condition is associated with their toxic metal burden . This macroepigenetic model proposes that autism prevalence is related to the consumption of HFCS and the overall exposure to Hg in the U.S. . However, other dietary factors associated with the consumption of HFCS may further contribute to the development of autism in the U.S.
Figure 1. The original Mercury Toxicity Model. The original Mercury Toxicity Model was published in 2009 by Dufault et al. in the Behavioral and Brain Functions journal. The model is a flow chart of what can happen in the body when there is exposure to mercury (Hg) from ingestion of foods (via HFCS, food colors and fish) or inhalation of air. Human neurodevelopment can be adversely impacted when MT gene expression is altered or suppressed by dietary transcription factors such as zinc (Zn) insufficiency or deficiency. Without proper MT expression and function, mercury excretion may not be possible and oxidative stress in the brain from mercury insult leads to reduced neuronal plasticity and impaired learning. Hg in fish is a problem when there is not enough selenium (Se) in the fish to counteract the Hg and the glutathione (GSH) system is disrupted leading to further oxidative stress.
Additional dietary factors associated with consumption of HFCS
U.S. per capita consumption of HFCS in 2009 was 35.7 pounds per year . The peak years for annual consumption of HFCS coincided with the peak growth rates of ASD in California, the only state that reports number of cases of ASD dating back to the mid-1980s . The Mercury Toxicity Model shows the HFCS characteristics most likely contributing to autism include the zinc-depleting effect that comes from consuming HFCS and certain food colors found in processed foods, and the additional Hg exposure that may occur from the low Hg concentrations sometimes found in HFCS as a result of the manufacturing process [4,17]. This model can be expanded to include additional adverse effects associated with the consumption of HFCS that likely contribute to the development of autism through PON1 gene modulation and lead intoxication.
U.S. Department of Agriculture (USDA) scientists warn that when dietary intake of magnesium (Mg) is low, consumption of HFCS leads to lower calcium (Ca) and phosphorus (P) balances adversely affecting macromineral homeostasis in humans . This is an unfortunate finding because there is evidence to suggest that dietary intake of Mg is low among Americans, most of whom consume a high fructose diet. In 2003, CDC scientists reported that substantial numbers of U.S. adults fail to consume adequate Mg in their diets . Children with autism were found to have significantly lower plasma Mg concentrations than normal subjects . Adams et al. found significant reductions in red blood cell (RBC) Ca, serum and white blood cell (WBC) Mg and an increase in RBC copper in autistic children as compared to controls . Recently, USDA scientists reported that the National Health and Nutrition Examination Survey (NHANES) data for 2005 to 2006 indicate that overall, nearly one half of all individuals one year and over had inadequate intakes of dietary Mg . With a substantial number of Americans consuming inadequate amounts of dietary Mg along with HFCS diets, one may predict that substantial numbers of Americans are likely experiencing a calcium (Ca) deficit as well.
Insufficient intake of dietary Ca, Mg and Zn, or losses or displacement of any of these minerals from the consumption of HFCS, may further enhance the toxic effects of lead (Pb) on cognitive and behavioral development in children . A significant and independent inverse relationship between dietary Ca intake and blood Pb concentrations was found in 3,000 American children examined as part of NHANES II . Elevated blood Pb levels are indicative of Pb intoxication, which is found in some children diagnosed with autism and associated with the development of ADHD [33,34]. It may be that inadequate intake of Ca or Mg combined with a HFCS zinc-depleting diet increases the risk of developing autism and ADHD from Pb intoxication.
Inadequate intake of Ca or Mg may further contribute to these developmental disorders by impacting human serum paraoxonase-1 (PON1) gene expression. PON1 is a calcium dependent enzyme responsible for OP pesticide detoxification as well as hydrolysis of the thiolactone form of homocysteine [35,36]. PON1 is synthesized in the liver and secreted in blood where it is incorporated into high density lipoproteins (HDL). The availability and catalytic activity of PON1 are impaired in many children with ASD making them more susceptible to the toxic effects of OP pesticide residues which are most frequently found in grain [37,38]. Figure 2 shows the expanded Mercury Toxicity Model that includes changes both in Pb toxicity and PON1 activity when dietary intake of Mg is low and consumption of HFCS leads to greater loss of calcium (Ca) and phosphorus (P), thereby adversely affecting macromineral homeostasis.
Figure 2. The expanded Mercury Toxicity Model. Figure 2 shows the expanding Mercury Toxicity Model that includes changes both in lead (Pb) toxicity and human serum paraoxonase (PON1) activity when dietary intake of Mg is low and consumption of high fructose corn syrup (HFCS) leads to lower calcium (Ca) and phosphorus (P) balances, adversely affecting macromineral homeostasis. With insufficient dietary intake of Ca and/or Mg, children become more susceptible to Pb intoxication and OP exposures with decreasing PON1 activity. Pb intoxication and OP exposures can both lead to oxidative stress in the brain reducing neuronal plasticity.
PON1 activity and organophosphate exposure in U.S
One can assert that with the consumption of a HFCS intensive diet and inadequate Mg intakes, PON1 activity may decrease, along with resulting Ca losses in genetically predisposed individuals. Although there are no human data yet to support this assertion, PON1 activity in rats decreased when fed a HFCS diet to mimic the human metabolic syndrome . PON1 activity has been extensively studied in humans and there are a number of factors known to modulate or alter PON1 expression including, but not limited to, Hg exposure, sex and age [40,41]. Age plays the most relevant role, as PON1 activity is very low before birth and gradually increases during the first few years of life in humans . In one study, scientists at UC Berkeley found the PON1 levels in many children may remain lower than those of their mothers for several years, especially those with genotypes associated with decreased PON1 activities . The scientists concluded that these children may be more susceptible to OP pesticides throughout their childhood and more vulnerable to conditions associated with oxidative stress such as autism . In a different study, scientists at UC Berkeley found that two-year-old children were less likely to display symptoms of PDD when their mothers had higher paraoxonase levels during their pregnancy . Proper function and adequate expression of the PON1 gene is essential both for prenatal development and child health because exposure to OP pesticides is a common occurrence in the U.S.
The CDC tracks exposure to OP pesticides or their metabolites through the National Biomonitoring Program (NBP). Exposure data are reported for the population as a whole and for subgroups. While most American groups are exposed to OP pesticides, children ages 6 to 11 have significantly higher exposures than adults and are at greatest risk from OP neurotoxicity . Harvard University researchers recently reported finding OP pesticide residues in a number of foods frequently consumed by children . The researchers expressed concern that the children were at times being exposed to multiple pesticide residues in single food commodities. OP pesticide exposures occur primarily from the consumption of foods containing pesticide residues.
It is well known that pesticide exposure can impair neurodevelopment in children, but recent studies have found that pesticide exposure during pregnancy can also cause delayed mental development in children . A review of epidemiological studies in 2008 found that prenatal and childhood exposure to OPs impairs neurobehavioral development . Higher concentrations of urinary dialkyl phosphate (DAP) measured during pregnancy was significantly associated with lower cognitive scores in children at seven years of age. Those children in the highest quintile of maternal DAP concentrations had an IQ score seven points lower than those children in the lowest quintile . In a group of newborns with the highest levels of the organophosphate chlorpyrifos measurable in their umbilical cord blood, birth weight averaged 150 grams less than the group with the lowest exposure . Prenatal pesticide exposure showed deficits consistent with developmental delays of 1.5 to 2 years .
Diet is the main source of OP exposure in children. Under the 1996 Food Quality Protection Act, the U.S. Secretary of Agriculture is directed to collect pesticide residue data on commodities frequently consumed by infants and children. USDA Pesticide Data Program (PDP) provides the residue data to comply with this law . We reviewed the PDP data from 2004 to 2008 and identified the foods most frequently found to contain organophosphate insecticide residues. In addition, we obtained the per capita availability data from the USDA to determine the amount of each food commodity the average American consumes . The results of our review indicate that wheat and corn are the commodities most likely contributing to OP exposure in U. S. children. Estimated per capita wheat consumption was approximately 95 pounds per year while estimated per capita corn consumption was approximately 23 pounds per year. The primary use of corn is for the production of corn sweeteners, such as HFCS; however, pesticide residue data were not gathered for this commodity by the PDP. Table 2 provides a complete breakdown of the results of this data review.
Table 2. PDP residue detections by year sampled wi th U.S. per capita consumption data
From Table 2 it is clear consumers are at risk of exposure to multiple OP pesticide residues from consuming the very same commodity. Cumulative exposures will continue to occur in the U.S. where OP pesticide use is widespread by the agricultural industry. Although OP pesticide use is equally widespread in other countries, there is genetic variation across populations that determine degree of susceptibility to OP exposure. The PON1 gene variants associated with autism in subgroups of the U.S. population but not in Italy could be attributed to the fact that HFCS consumption rarely occurs in Italy, thereby lessening the conditions for PON1 modulation.
HFCS consumption and PON1 modulation in autism in the U.S
In the 27-member European Union (EU), of which Italy is an original participant, HFCS is known as “isoglucose” and currently it is rarely consumed by Italians. Americans on the other hand consume on average 35.7 pounds per year, which may increase their overall Hg exposure [17,25]. Figure 3 shows U.S. per capita food consumption in pounds per year for HFCS beginning in the early 1970s and increasing throughout the 1980s to reach a peak between 1999 and 2002. In our previous publication, we reported the peak years for annual consumption of HFCS in the U.S. occurred within the same period as when the annual growth rates of autism peaked in California .
Figure 3. U.S. per capita consumption of high fructose corn syrup 1966-2004. Figure 3 shows the United States (US) per capita consumption of high fructose corn syrup (HFCS) in pounds per year as calculated by the United States Department of Agriculture (USDA)/Economic Research Service.
American per capita consumption of HFCS has exceeded 20 pounds per year since 1980 while Italians consume negligible amounts of the same ingredient. As was previously mentioned, mercury (Hg) and fructose may both modulate PON1 activity [39–41]. While excessive fructose exposure in the U.S. may primarily occur through the consumption of foods containing HFCS, mercury exposure may occur in a number of ways. A comparison of common sources of mercury exposure in the U.S. and Italy may offer a further explanation of the PON1 gene variation associated with autism in the U.S. but not in Italy.
In addition to HFCS, primary sources of inorganic and elemental Hg exposure may occur from consumption of food colors and preservatives made with mercury-cell chlorine or chlor-alkali products, seafood consumption, Hg in dental amalgam, thimerosal in vaccines, and depending on geographic location, inhalation of Hg contaminated air [4,51–54]. Children living near coal-fired power plants are often exposed to higher levels of Hg in their breathing air and have a higher prevalence of autism . Because Hg emissions from coal-fired power plants are not yet regulated in either the U.S. or Italy, this particular source of Hg exposure is unlikely to explain the overall difference in autism prevalence between these two countries. With respect to the consumption of seafood, use of Hg dental amalgam, thimerosal in vaccines or Hg-containing food colors and preservatives, there is also no appreciable difference between Italy and the U.S. [56–58]. The only remaining variable in our model is the excessive consumption of HFCS by Americans, which results in greater chronic exposures to both inorganic Hg and, by definition, fructose .
Inorganic Hg may interact with cysteine residues on PON1 preventing its activation in the liver and impairing the body’s ability to protect itself against OP pesticides and oxidative stressors involved in autism . As noted above, PON1 is responsible for hydrolysis of homocysteine thiolactone, and plasma PON1 activity is negatively correlated with homocysteine levels [36,59]. Homocysteine is a metabolic biomarker for oxidative stress and impaired methylation capacity. A recent study of the Inuit population found a significant inverse correlation between PON1 activity and Hg levels, as well as a direct correlation with selenium levels . With increasing Hg and fructose exposure and reductions in dietary Ca, one can expect to see reduced PON1 activity and increasing homocysteine levels in children with ASD.
Indeed, Pasca et al. recently reported finding that both PON1 arylesterase and PON1 paraoxonase activities were decreased in children with autism [61,62]. James et al. found that children with autism had higher plasma homocysteine levels than controls but demonstrated significant improvements in transmethylation metabolites and glutathione (GSH) after receiving folate and vitamin B12 . Patel and Curtis found that in addition to glutathione and B12 injections one to three times per week, children with autism and ADHD showed significant improvement in many areas of social interaction, concentration, writing, language and behavior when fed an organic diet low in fructose and free of food additives and food colors .
Mothers of autistic children in the U.S. were also found to have significant increases in mean plasma homocysteine levels compared to controls . Schmidt et al. found that women who took vitamin supplements during the periconceptional period reduced the risk of autism in their children . Those women who did not take vitamins during
this period were more likely to have a child with autism and were at even greater risk when they had specific genetic variants within one-carbon metabolism pathways. This suggests that folate and other dietary methyl donors may alter epigenetic regulation of gene expression in their children, thereby reducing the risk of autism .
Methionine synthase links oxidation to epigenetics
Epigenetic regulation of gene expression is highly dependent upon methylation of both DNA and histones, and methylation capacity is in turn dependent upon activity of the folate and vitamin B12-dependent enzyme methionine synthase, which converts homocysteine to methionine. Lower methionine synthase activity decreases the level of the methyl donor S-adenosylmethionine (SAM) while simultaneously increasing the level of the methylation inhibitor S-adenosylhomocysteine (SAH) . The combined effect of changes in the SAM to SAH ratio, therefore, exerts a powerful influence over more than 200 methylation reactions, including DNA and histone methylation .
Methionine synthase activity is inhibited by oxidative stress, and its inhibition results in the diversion of homocysteine to produce the antioxidant glutathione (GSH), providing an important adaptive response . However, oxidative inhibition of methionine synthase leads to epigenetic effects via the resultant decrease in the SAM to SAH ratio and decreased DNA and histone methylation. Epigenetic changes in gene expression can recruit further adaptive responses to oxidative stress. Figure 4 illustrates how these changes may occur when the body is under oxidative stress from exposure to OP pesticides, heavy metals, and calcium depleting substances, such as HFCS. Decreased methionine synthase activity during oxidative stress also increases homocysteine thiolactone formation , raising the importance of PON1. As was previously mentioned, PON1 is essential for reducing homocysteine levels, which are thought to be harmful. Elevated plasma homocysteine (tHcy) levels are associated with genome-wide DNA hypomethylation that may carry over from one generation to the next, increasing the risk of autism . Epigenetic changes affecting germline cells can give rise to these transgenerational effects . James et al. found that parents share similar metabolic deficits in methylation capacity and glutathione-dependent antioxidant/detoxification capacity with their children with autism .
Figure 4. Methionine synthase links oxidative stress to epigenetic regulation. Figure 4 shows how exposure to toxic substances, such as OP pesticides, HFCS, or heavy metals, inhibits methionine synthase through effects of oxidative stress. As a result, decrease of SAM to SAH ratio will lead to a decrease in DNA methylation and consequently to altered PON1 gene expression.
Synergistic effect of multiple neurotoxins
Based upon the discussion above, it is clear that methionine synthase activity is crucial for translating changes in oxidative status into epigenetic effects, and this role is confirmed by the improved metabolic profile in autistic subjects given folate and vitamin B12 . This relationship has given rise to the “Redox/Methylation Hypothesis of Autism”, which proposed that oxidative insults arising from environmental exposures, such as Hg and pesticides, can cause neurodevelopmental disorders by disrupting epigenetic regulation . The macroepigenetic Mercury Toxicity Model expanded in this paper provides additional support for the “Redox/Methylation Hypothesis of Autism” while contributing important insight into the oxidative stress feedback mechanisms that may occur as a result of malnutrition resulting from dietary exposures to toxins. The delivery of children exhibiting autistic behaviors might be associated with the prenatal diet of their mothers. The severity of these behaviors can be further exacerbated by toxic dietary exposures of the children, which can improve with dietary changes aimed at eliminating these exposures. Children with autism could well be exhibiting an epigenetic response to several neurotoxic substances at once, including, but not limited to, inorganic Hg, Pb, OP pesticides and/or HFCS. The combined effect of these substances acting together is likely greater than the sum of the effects of the substances acting by themselves. This effect likely reduces neuronal plasticity and impairs learning capacity in autistic children.
The number of children ages 6 to 21 in the U.S. receiving special education services under the autism disability category increased 91% between 2005 to 2010 despite fewer children receiving special education services overall during the same time period. A comparison of autism prevalence between the U.S. and Italy using the Mercury Toxicity Model suggests the increase in autism in the U.S. is not related to mercury exposure from fish, coal-fired power plants, thimerosal, or dental amalgam but instead to the consumption of HFCS. Consumption of HFCS may lead to mineral imbalances, including Zn, Ca and P loss and Cu gain and is a potential source of inorganic mercury exposure. These mineral imbalances create multiple pathways for oxidative stress in the brain from exposure to OP pesticides and heavy metals, such as Pb or Hg. Inorganic mercury and fructose exposure from HFCS consumption may both modulate PON1 gene expression. With a reduction in PON1 activity, there is a potential for increasing homocysteine levels which are associated with genome-wide DNA hypomethylation that may carry over from one generation to the next, affecting both neurodevelopment and autism prevalence.
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