Since TCDD has teratogenic and mutagenic effects, what genes does it affect?
“Arylhydrocarbon receptor (Ahr) activation by 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) interferes with female reproductive functions…” as stated in a study (1) found on the NCBI website, is a good place to look for genetic generational effects, because it is also known that AhR’s oldest physiological purpose is for organism development and regulating gene expression. The study goes on to say, “Importantly, activation of the Ahr pathway also interferes with Esr pathways through a number of mechanisms” and that “we tested interactions between TCDD and E2 on the regulation of genes encoding Esr1, Ahr, Prl, as well as Lhb and Cga subunits.” This study gives great insight towards possible genes to look at for areas of transgenerational effects of Agent Orange. Which is exactly what we began to do, and in our preliminary research, yes, we have detected variants in these genes, but more data of those in the line of exposure, from direct to subsequent generations, is needed.
Not only did we look at the genes from the previously mentioned study, but we also looked at genes from another study (2), which listed ten dioxin detoxification genes to be examined. In their study, they were trying to find a correlation between endometriosis and it’s possible link to the genes that are associated with dioxin detoxification, because there is a high rate of endometriosis in those in the line of exposure to TCDD/dioxin. The study participants included 100 patients with endometriosis and 143 controls, but exposure to dioxin was not a consideration for categorization in this particular study. So, it doesn’t answer the question as to whether dioxin exposure affects these genes, in turn resulting in the cases of endometriosis. What this study does provide though, is a starting point for other studies to fill in the information gap on participants that have been exposed and/or in the line of exposure and the possible affects of dioxin on these particular genes. In the end, they conclude that additional studies on different female populations are required and that using a classification such as exposure of patients to dioxin, could help to overcome problems of misrepresentation.
Our preliminary research, on the genes from these two studies, did reveal variants, but more research and participant data is necessary to consider any particular variants as linked to exposure.
The genes include:
WNT4- Part of a gene family related to genes that encode proteins that have been implicated in developmental processes, including regulation of cell fate and patterning during embryogenesis
CDKN2BAS- This genes’ product is a functional RNA molecule that interacts with polycomb repressive complex-1 (PRC1) and -2 (PRC2), leading to epigenetic silencing of other genes in this cluster. This region is a significant genetic susceptibility locus for cardiovascular disease, and has also been linked to a number of other pathologies, including several cancers, intracranial aneurysm, type-2 diabetes, periodontitis, Alzheimer's disease, endometriosis, frailty in the elderly, and glaucoma.
PRC1- This gene encodes a protein that is involved in cytokinesis, where it ensures that chromosome number and complement are maintained from one generation to the next and that, except in special cases, the daughter cells will be functional copies of the parent cell.
NFE2L3- The encoded protein from this gene heterodimerizes with small musculoaponeurotic fibrosarcoma factors to bind antioxidant response elements in target genes.
HOXA10- This gene encodes a DNA-binding transcription factor that may regulate gene expression, morphogenesis, and differentiation. More specifically, it may function in fertility, embryo viability, and regulation of hematopoietic lineage commitment.
AhR- The protein encoded by this gene is involved in the regulation of biological responses to planar aromatic hydrocarbons. This receptor has been shown to regulate xenobiotic-metabolizing enzymes. The encoded protein moves to the nucleus and stimulates transcription of target gene.
AHRR-The protein encoded by this gene participates in the aryl hydrocarbon receptor (AhR) signaling cascade, which mediates dioxin toxicity, and is involved in regulation of cell growth and differentiation.
ARNT- This gene encodes a protein that binds to ligand-bound aryl hydrocarbon receptor and aids in the movement of this complex to the nucleus, where it promotes the expression of genes involved in xenobiotic metabolism.
CYP1A1- This gene has been associated with lung cancer risk.
CYP2E1- Diseases associated with CYP2E1 include Alcoholic Liver Cirrhosis and Fatty Liver Disease. This gene encodes an enzyme that may be involved in such varied processes as gluconeogenesis, hepatic cirrhosis, diabetes, and cancer.
EPHX1- Diseases associated with EPHX1 include Hypercholanemia, Familial and Cystic Fibrosis.
GSTM1- This gene encodes enzymes that function in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress.
GSTP1- Diseases associated with GSTP1 include Barrett Esophagus and Oligoasthenoteratozoospermia.
GSTT1-(GST Family) May play a role in human carcinogenesis. The GSTT1 gene is haplotype-specific and is absent from 38% of the population.
NAT2- Polymorphisms in this gene are associated with higher incidences of cancer and drug toxicity.
PRL- Encodes a pituitary hormone that is a growth regulator for many tissues, including cells of the immune system, may also play a role in cell survival by suppressing apoptosis, and it is essential for lactation.
LBH- A regulator of the WNT signaling pathway.
SYCE1- Allelic variants of this gene have been associated with premature ovarian failure and spermatogenic failure.
Esr1-This gene encodes an estrogen receptor, composed of several domains important for hormone binding, DNA binding, and activation of transcription.
If you are in the line of exposure to Agent Orange and have had DNA testing that reflects variants/mutations in these genes, take our survey for Self Reported Variants/Mutations, or contact us if you would like to share your raw genetic data with us. We utilize Sequencing.com data analysis and their system can accept raw data from any genetic test, including raw data from doctors offices and places like Ancestry.com, 23andMe, Familytreedna, and many others. If you are wanting to obtain genetic testing, both Sequencing.com and Dante Labs provide clinical grade whole genome sequencing and analytics that provide actionable health information.
ACKKNOWLEDGEMENTS:
(1) Cao J, Patisaul HB, Petersen SL. Aryl hydrocarbon receptor activation in lactotropes and gonadotropes interferes with estradiol-dependent and -independent preprolactin, glycoprotein alpha and luteinizing hormone beta gene expression. Mol Cell Endocrinol. 2011 Feb 20;333(2):151-9. doi: 10.1016/j.mce.2010.12.027. Epub 2010 Dec 25. PMID: 21187122; PMCID: PMC3059512.
(2) Matsuzaka Y, Kikuti YY, Goya K, Suzuki T, Cai LY, Oka A, Inoko H, Kulski JK, Izumi S, Kimura M. Lack of an association human dioxin detoxification gene polymorphisms with endometriosis in Japanese women: results of a pilot study. Environ Health Prev Med. 2012 Nov;17(6):512-7. doi: 10.1007/s12199-012-0281-y. Epub 2012 May 1. PMID: 22547312; PMCID: PMC3493626.
GeneCards: The Human Gene Database: “GeneCards is a searchable, integrative database that provides comprehensive, user-friendly information on all annotated and predicted human genes. The knowledgebase automatically integrates gene-centric data from ~150 web sources, including genomic, transcriptomic, proteomic, genetic, clinical and functional information.”