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Our study shows the magnitude of what can happen if topoisomerases are impaired,” said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC. “Inhibiting these enzymes has the potential to profoundly affect neurodevelopment — perhaps even more so than having a mutation in any one of the genes that have been linked to autism.”
The study could have important implications for ASD detection and prevention.
“This could point to an environmental component to autism,” said Zylka. “A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. ”
This study could also explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders.
Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.
Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells. “If there are additional compounds like this in the environment, then it becomes important to identify them,” said Zylka. “That’s really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects — so that pregnant women can avoid being exposed to these compounds.”
Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy.
Investigating the drug’s effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long — composed of many DNA base pairs. The group then made the serendipitous connection that many autism-linked genes are extremely long.
“That’s when we had the ‘Eureka moment,’” said Zylka. “We realized that a lot of the genes that were suppressed were incredibly long autism genes.
The autism group had significantly higher levels of lead in their red blood cells (+41 percent) and significantly higher urinary levels of lead (+74 percent), thallium (+77 percent), tin (+115 percent), and tungsten (+44 percent). Lead, thallium, tin, and tungsten are toxic metals that can impair brain development and function, and also interfere with the normal functioning of other body organs and systems.
A statistical analysis was conducted to determine if the levels of toxic metals were associated with autism severity, using three different scales of autism severity. It was found that 38-47 percent of the variation of autism severity was associated with the level of several toxic metals, with cadmium and mercury being the most strongly associated.
When ingested, they combine with the body’s biomolecules, like proteins and enzymes to form stable biotoxic compounds, thereby mutilating their structures and hindering them from the bioreactions of their functions.
Meta Analysis Source
In another reviewed study, exposure to ethylmercury (thimerosal) led to a larger increase in free radical generation and a greater reduction in the ratio of reduced GSH to GSSG in ASD cells compared with control cells.35 These findings suggest that mitochondria from children with ASD may be more vulnerable to damage from environmental toxicants than mitochondria from typically developing children.35 In this context, exposures to environmental toxicants could contribute to secondary mitochondrial dysfunction in some children with ASD.9, 201 For example, in vitro exposure to diesel exhaust particles has been shown to inhibit mitochondrial function,80 and elevated environmental concentrations of diesel exhaust particles have been associated with ASD.202 Other environmental toxicants that inhibit mitochondrial function and have been associated with ASD include mercury, lead, cadmium, polychlorinated biphenyls and pesticides.
Interestingly, some investigators have suggested that mtDNA deletions reported in some children with ASD may be secondary to elevated levels of ROS (oxidative stress) caused by environmental factors.
Abnormalities in synaptic transmission reported in ASD could also contribute to secondary mitochondrial dysfunction. For example, an imbalance in the excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmitter systems has been implicated in the pathogenesis of ASD, with a relative increase in the glutamatergic neurotransmitter system.
I know that many people will say the vaccine issue has been thoroughly investigated and debunked. I honestly wish that were the case, but it simply is not true. All of the "vaccine-autism" studies you hear about investigated just one childhood vaccine out of 14 (MMR), or one vaccine ingredient out of dozens (thimerosal). That is like announcing that air pollution does not cause lung cancer because you looked at carbon monoxide, alone, and hydrogen sulfide, alone, and found no link.
MetaAnalysis - quote on page 28
In another reviewed study, exposure to ethylmercury (thimerosal) led to a larger increase in free radical generation and a greater reduction in the ratio of reduced GSH to GSSG in ASD cells compared with control cells.35 These findings suggest that mitochondria from children with ASD may be more vulnerable to damage from environmental toxicants than mitochondria from typically developing children.35 In this context, exposures to environmental toxicants could contribute to secondary mitochondrial dysfunction in some children with ASD.
reply to post by AboveBoard
One of the really cool things about epigenetic mechanisms and changes is that they can be inherited without changing DNA. Another awesome reality is that inherited or acquired epigenetic changes are reversible.
So there is much hope.
It's becoming very well known in the research community that many "new" diseases like autism and other chronic conditions result from environmental effects. [Note: In biology, "environmental" refers to both the cellular environment and the larger external environment.] Simply put, stuff in the environment affects epigenetic mechanisms - causing genes to be turned off and on, and changing gene products (proteins) after they are produced - so that our cells and bodies can respond and adapt to our immediate environments.
...So my pet peeve is when "they" say a disease is "genetic" - because it's usually not. It's epigenetic and there is nothing at all wrong with your bloodline or genes.
Also, the term "genetic predisposition" is totally misleading - epigenetics controls gene expression, and has to do with environmental exposures. Except in very rare cases involving genetic mutations, there is nothing "wrong" with the genes themselves.
....no study has looked at the combined effect of gene expression, AND environmental factors such as those described thus far.
Environmental induced epigenetic transgenerational inheritance of disease
Summary: Biological science is undergoing a paradigm shift away from the fixed genetic determinism of the 20th century and toward an understanding that environmental factors can alter gene expression and activity. Genetics works together with the environment to contribute to disease risk. In some cases, changes to gene expression in future generations can occur when the germ cell (sperm or egg) is reprogrammed via an abnormal exposure such as an endocrine-disrupting compound, and these alterations may persist for generations. This transgenerational exposure to environmental factors represents an example of epigenetic inheritance. Various pathologies may result from certain germline exposures, including cancer, infertility, polycystic ovary disease, obesity, and behavioral abnormalities. Assays find clusters of altered gene expression dependent on the original exposure, or dependent on the generation studied.
How might epigenetics relate to the etiology of ASD?
Summary: Various epigenetic mechanisms may contribute to ASD traits and there is growing evidence for environmental susceptibility of epigenetic marks. Studies show that phenotype and epigenetic marks can be modified by factors such as maternal diet, pharmaceuticals, and smoking, and metals and behavior. The epigenome may be the intermediary between genetics and the environment, mediating disease outcome. Existing research supports a role for epigenetics in ASD etiology, for example with ASD-related disorders with known epigenetic mechanisms, parent-of-origin effects, differences of expression in ASD-related genes, and differences in methylation patterns.
Prenatal exposures: An unrecognized multigenerational epidemic
Summary: Historically, the placenta was viewed as a barrier preventing passage of harmful substances to the fetus. However, today we know that organ acts more like a sieve, with most maternally ingested substances reaching fetal tissues. Prenatal use of synthetic medications goes back a century, beginning with barbiturates and then synthetic hormones, including synthetic estrogens (including the catastrophic drug DES) progesterones, and corticosteroids. In the mid 20th century, synthetic hormone drugs were widely used in pregnancies deemed to be “at risk,” and as a result millions of offspring were exposed to augmented levels of synthetic or natural hormones. The exposures are associated with a variety of disruptions of typical development; however, drug impacts on fetal germ tissues (grandchild, or F2, generation) have not yet been assessed. A study using the Danish Prenatal Development Project, which is unusually rich with prenatal exposure data, will be the first to examine potential germline/F2 impacts of prenatal drug use.
Studies map gene expression across brain development
21 November 2013
Now that genetic studies have implicated several hundred genes in autism, researchers are turning their attention to where and when in the healthy young brain these genes are expressed. The first two studies to tackle these questions appear today in Cell.
...."Autism is an extremely complex disease where the environment is playing on an unfolding genetic program," Molnár says. "We shouldn't ignore some of the systems which might feed into this."
The fact that there are so many expressions of Autism, and so many potential causes, all of which must be checked out thoroughly, is what makes this whole thing so damned tricky.
First of all, where the vaccine related autism issue is concerned, no studies have been done to examine the effects of combinations of various vaccines over a ten year period from birth of a child upward. Nor have any experiments been run, to my knowledge, which would seek to replicate that experience in lab mice, monkeys, or any other such thing.
TrueBritThis makes environmental causes, as opposed to genetic ones, a legitimate target for further, very depthy research. Also, no study has looked at the combined effect of gene expression, AND environmental factors such as those described thus far. Furthermore, no statistical research is going to be able to help, because the pharma companies which deal with the sorts of drugs which have been previously linked to autism in its various guises, have been doing their damnedest to cover their butts on this issue since I was a nipper.
There are an awful lot of chips stacked up against this issue, and all I can say is that I hope the dealer has a fair hand.
One hundred years ago, children received 1 vaccine (the smallpox vaccine). Forty years ago, children received 5 vaccines routinely (diphtheria, pertussis, tetanus, polio, and smallpox vaccines) and as many as 8 shots by 2 years of age. Today, children receive 11 vaccines routinely and as many as 20 shots by 2 years of age (Table 1). The increased number of vaccines given to children and the increased percentage of children receiving vaccines have resulted in a dramatic decrease in the number of vaccine-preventable diseases. Most young parents today have never seen many of the diseases that vaccines prevent. As a possible consequence of these trends, recent national surveys found that 23% of parents questioned the number of shots recommended for their children,1 and 25% were concerned that vaccines might weaken the immune system.1