Evaluate recent research regarding the role of dioxin in liver and thymus damage in humans.

Dioxins are an unwanted by-product of many industrial processes including pesticide manufacturing, pulp and paper bleaching and burning plastics. The most potent and dangerous of these chemicals, 2, 3, 7, 8-tetrachloro-dibenzo-para-dioxin (TCDD), that is extremely difficult for the body to get rid of, due to their highly hydrophobic properties, therefore highly soluble in fats. Wide ranges of varying effects have been observed with animals exposed to varying levels of dioxins, in particular the dioxin 2,3,7,8-TCDD. There has been extensive on-going research regarding the effects of dioxins on certain animals to ascertain the integral biochemical factors related to dioxins and their potency in the hope that these effects may be maintained and prevented. How are we exposed to dioxins? Dioxin exposure is primarily associated with diet as well as inhalation of atmospheric dioxin.

It has been recognized that dioxin exposure can cause liver and thymus damage in human. Revealed by recent experiment in January, 2011, microRNA (miRNA) is responsible for inducing liver damage in mice exposed to TCDD by reducing the miR-101a expression levels of prostanoid signaling pathway catalyzed by COX-2, and then the elevated levels of prostanoid cause the liver damage. Based on the recent research study by Yoshioka, Higashiyama and Tohyama (2011) on mouse model found hepatic hydropic changes, infiltration of F4/80 positive cells, increased activity of hepatic enzyme in the serum and apoptosis at 14-day postadminitration. Besides, a single intraperitoneal injection of TCDD increased plasma AST level at day 6 postadministration and thereafter. The liver weight increased by 14% in response to TCDD. These results indicated that the TCDD-exposed mice were free of overt abnormalities in the first 4 days, liver damage became apparent around day 6 and then progressed and finally, body weight started to decline around day 14 when liver damage perceived.

According to them, when miR-101a was reduced, the expression level of COX-2 at mRNA and protein levels was increased as well as an increased in EZH2 and cFos at protein level. This suggests that the altered expression levels of miR-101a, COX-2, EZH2 and cFos had been sustained from day 2 postadministration. Exposure to TCDD downregulates the expression

of miR-101a which then causes the upregulation of the COX-2 expression that is related to the onset of the liver damage. Researched utilized NS-398, a COX-2 selective inhibitor, did not affect the reduction of miR-101a by TCDD which is in line with the hypothesis; TCDD downregulates the expression of miR-101a which then causes the upregulation of the COX-2 expression.

Dioxin exposure shows significant changes in the expression levels of miR-101a and miR-122 in the liver of TCDD exposed mice. Reduction in the expression level of miR-101a was evident as early as day 2 and leveled off at least until day 14 postadministration, whereas the reduction in the expression level of miR-122 was detected only at day 14. The expression levels of these miRNAs fluctuated minimally within each group of the mice. MiR-122 acts as a regulatory role in lipid metabolism. Studies raise the possibility that the reduction of the miR122 expression level by TCDD exposure is involved in the dysregulation of lipid metabolism elicited by dioxin. TCDD reduced miR-122 expression level at day 14 postadministration, but not at day 2, which indicated that the reduction of miR-122 expression level is a secondary effect, because other physiological changes such as the induction of CYP1A1, a prototypical indicator of AhR action, occurs within 1-day postadministration. MiR-122 expression level decreased in the acetaminophen-damage liver.

In control groups, CV values of the expression levels of miR-101a and miR-122 ranged from 5.9 to 12.9%, and in TCDD-exposed groups, the miRNA levels CV values from 9.8 to 10.0%. This demonstrated that the expression levels of the miRNAs are strictly regulated under nonstimulated and TCDD-exposed conditions, which was confirmed by the reliable measurement of miRNAs by the PAP RT-PCR method. Besides that, the experiment also indicated that the amounts of miRNAs are precisely tuned to regulate biological pathways but how reduction of miR-101a expression level associated with damage in the liver? COX-2 is a well-established target of miR-101a. 3 UTR of mRNA has a binding sequence of miR-101a, and a reporter gene having this binding sequence is downregulated in response to the overexpression of miR-101a in a binding sequence specific manner. COX-2, EZH2 and cFos proteins were all

increased at the same time suggested; existence of a common upregulation mechanism for these three genes. Increase of COX-2 mRNA alone could either be the consequence of variation in their binding sequence of miR-101a, or effects of other mechanisms involved in COX-2 gene regulation, such as nongenomic action of AhR that exerts calcium-dependent rapid mechanism in the cytoplasm to upregulate COX-2 mRNA. The reduced expression level of miR-101a by TCDD is considered to account for the common upregulation of these target genes. Strongly support the existence of post-transcriptional regulation of COX-2, EHZ2 and cFos mediated by miR-101a in the mouse liver exposed to TCDD.

EZH2; increased by TCDD exposure, is methyltransferase that transfers methyl groups to lysine 27 of histone H3 (H3K27). Resulting H3K27 trimetylation leads to the transcriptional repression of target genes, including several genes of the Wnt family. EZH2 could be an important molecule that links AhR and Wnt in the toxicity of dioxin. Hypoplasia of the lymphoid organs is often observed at relatively high doses. Recent study demonstrated that prenatal exposure to PCB #118 which has limited ability to bind to the AhR, leads to hypoplasia of the gastric-associated lymph nodes. Some of the effects on immune system have recently been shown to be extremely persistent. Previously suggested in studies of prenatal effects on the immune system in mice, thymocyte differentiation is altered in mice prenatally exposed to dioxin. One of the recognized toxicities is liver and thymus damage in humans that are mediated by transcription factor, Ah receptor (AhR). Revealed by recent experiments using AhR-null mice, in which no such toxicities were produced. Dioxin exposure elicits the upregulation of a large number of genes in an AhR-dependent manner, and it is predicted that some of these AhR target genes are directly responsible for the induction of dioxin toxicities.

In conclusion, based on the research study conducted by Yoshioka, Higashiyama and Tohyama (2011) suggest that dioxin plays a major role in regulating and altering specific miRNAs, miR-101a and miR-122. Therefore COX-2 alteration occurred that was significantly involved in TCDD-induced hepatic damage as well as one of the causes to thymus damage. Dioxin effects or dioxin-like PCBs, require AhR. Function of this receptor syatem is similar to

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