Steps Down the Path to Proving How "Toxins" Cause Disease - Researchers Find Dioxin Impacts on MicroRNA in Fetal Mice : GlobalTort

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Steps Down the Path to Proving How "Toxins" Cause Disease - Researchers Find Dioxin Impacts on MicroRNA in Fetal Mice

Posted on September 18, 2012 by Kirk Hartley

Molecular biologists continue to delve into the specifics of how "toxins" cause harm, thus creating information that someday will end up as part of toxic tort litigation. Working with funds from NIH and the Veterean's Administration, researchers at the University of South Carolina have now published findings of dioxin causing changes to the patterns of microRNA expressed in fetal mice when the mother is exposed to dioxin. The changes appear to matter biologically because microRNA regulate (control) the work of various genes, including genes related to the occurrence of cancers and other diseases. The microRNA changes found here include changes to microRNA tied to cell signaling pathways specifically known to involve diseases such as cancer. The findings thus represent a step down the path of explaining the full biology of why dioxin is "toxic." The pattern of microRNA changes also may - after more work - prove to be a means of fingerprinting a cause of harm in a particular creature.

The paper is: Narendra P. Singh, Udai P. Singh, Hongbing Guan, Prakash Nagarkatti, Mitzi Nagarkatti. Prenatal Exposure to TCDD Triggers Significant Modulation of microRNA Expression Profile in the Thymus That Affects Consequent Gene Expression. PLoS ONE, 2012; 7 (9): e45054 DOI: 10.1371/journal.pone.0045054. ScienceDaily also provides a summary and links.

A press release from the University of South Carolina explains the findings as follows:

"Research carried out at the University of South Carolina has identified novel mechanisms through which dioxin, a well-known environmental contaminant, can alter physiological functions, according to a study published online in the journal PLOS ONE.

The research team, which included Narendra Singh, Mitzi Nagarkatti and Prakash Nagarkatti of the USC School of Medicine, demonstrated that exposure to dioxin (TCDD) during pregnancy in an experimental mouse model can cause significant toxicity to the fetus, and specifically to the organs that produce the immune cells that fight infections. They found that dioxin alters small molecules called microRNAs, which can affect the expression of a large number of genes.

The study examined over 608 microRNAs, and 78 of these were significantly altered following exposure to dioxin. On the basis of the pattern of changes in these molecules, the team was also able to predict that dioxin can alter several genes that regulate cancer. Many other physiological systems were also affected, including those involved in reproductive, gastrointestinal, hematological, inflammation, renal and urological diseases as well as genetic, endocrine and developmental disorders.

Dioxin is a highly toxic chemical produced as a byproduct of industrial processes, such as the manufacture of herbicides or pesticides or the bleaching of paper. Because it degrades slowly in the environment and is soluble in fats, dioxin can bio-accumulate in the food chain and is often found in high concentrations in the milk and fat of animals in contaminated regions.

“Our results lend more credence to the hypothesis that fetal exposure to environmental contaminants can have life-long effects,” said Mitzi Nagarkatti. “Prenatal damage to the expression of microRNAs in the immune system could well impact the adult immune response.”

For more on microRNA's and their roles, note the following explanations from the article:

"The biological significance of miR generation is evident by their ability to regulate gene expression causing serious effects on various physiological, pathological, and other biological mechanisms and functions. The miRs have been shown to regulate up to 30% of the mammalian genes [3] suggesting that most cellular pathways are potentially regulated by miRs [4], [5], [6]. The effect of miRs can be of various degrees from mild to very strong. The strong effect of miRs is evident from the lethality of knockout mice that lack any of the enzymes responsible for miR production, such as Ago2, Dicer, and Drosha. Some of cellular processes regulated by miRs include apoptosis, cell growth, fat storage, insulin secretion, and cancer initiation and progression [4], [5], [6]. miRs may play a significant role in responses to xenobiotic chemicals and their role in causing various health associated problems and ailments. Fukushima et. al. have shown that exposure of rats to liver toxicants such as acetaminophen or carbon tetrachloride caused alteration in the expression of various miRs [7]. In another report, tamoxifen, a potent hepatocarcinogen, was shown to increase the expression of several miRs associated with oncogenes [8]. There are reports demonstrating that cigarette smoking can cause changes in miR expression profile [9]. It has also been shown that mothers smoking cigarettes can exhibit changes in expression levels of miRs related to growth and developmental processes [10]. Similarly, other chemicals, such as bisphenol A, have been shown to cause alteration in miR expression in vitro [11]. There are also reports suggesting that drug-metabolizing enzymes such as CYP family genes are targeted by certain miRs [6], [12]. These reports suggest that miRs may regulate the toxicity mediated by environmental chemicals.

TCDD (Dioxin) belongs to a group of halogenated aromatic hydrocarbons and is well known for its immunotoxic and carcinogenic properties [13], [14], [15], [16], [17], [18], [19], [20]. Recent epidemiological and experimental evidence has led to the advancement of “the fetal basis of adult disease” hypothesis, which suggests that malnutrition or exposure to environmental stress during pregnancy, may have a long lasting impact on the developing fetus, leading to increased susceptibility to a wide range of diseases later in life, including cancer, hypertension, cardiovascular, and autoimmune diseases [21], [22]. We and others have shown that exposure to TCDD during pregnancy severely affects the immune system of the mothers and their fetuses by triggering apoptosis in thymic T cells, altering T cell subsets and functions, as well as expression of co-stimulatory molecules [14], [23]. The majority of biological effects of TCDD leading to immunotoxicity and associated deleterious effects are mediated by aryl hydrocarbon receptor (AhR) [24]. The necessity of AhR for TCDD-induced toxicity was revealed by experiments using AhR-null mice, which exhibited resistance to toxicity [25], [26], [27]. TCDD exposure elicits the upregulation of a large number of genes in an AhR-dependent manner [28] and it is predicted that some of these AhR target genes are directly responsible for the induction of dioxin toxicity."

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