The possible roles of environmental factors and the aryl hydrocarbon receptor in the prevalence of thyroid diseases in Vietnam era veterans

Spaulding, Stephen W.

doi:10.1097/med.0b013e32834a8764

Cited by 24 publications

(12 citation statements)

References 33 publications

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“…For example, Vietnam War Veterans exposed to the Agent Orange descendants may currently be experiencing an increased incidence of disease [7]. The toxic effects of direct exposure to dioxin include acute liver damage, weight loss, thymic atrophy, immune suppression and chronic diseases, as well as lymphomas and leukemias in humans [6]. The list of diseases seen following exposure of war veterans to Agent Orange (herbicide contaminated with dioxin) during the Vietnam era is growing [7].…”

Section: Discussionmentioning

confidence: 99%

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Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations

et al. 2012

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Environmental compounds can promote epigenetic transgenerational inheritance of adult-onset disease in subsequent generations following ancestral exposure during fetal gonadal sex determination. The current study examined the ability of dioxin (2,3,7,8-tetrachlorodibenzo[p]dioxin, TCDD) to promote epigenetic transgenerational inheritance of disease and DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to dioxin during fetal day 8 to 14 and adult-onset disease was evaluated in F1 and F3 generation rats. The incidences of total disease and multiple disease increased in F1 and F3 generations. Prostate disease, ovarian primordial follicle loss and polycystic ovary disease were increased in F1 generation dioxin lineage. Kidney disease in males, pubertal abnormalities in females, ovarian primordial follicle loss and polycystic ovary disease were increased in F3 generation dioxin lineage animals. Analysis of the F3 generation sperm epigenome identified 50 differentially DNA methylated regions (DMR) in gene promoters. These DMR provide potential epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Observations demonstrate dioxin exposure of a gestating female promotes epigenetic transgenerational inheritance of adult onset disease and sperm epimutations.

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Section: Discussionmentioning

confidence: 99%

“…In rodents TCDD has a half-life of weeks and causes liver disease, weight loss, thymic atrophy and immune suppression. In humans direct dioxin exposure influences chronic diseases, lymphomas and leukemias [6]. The half-life of TCDD in humans varies to over 10 years with body mass index, age, sex and exposure concentration [7].…”

Section: Introductionmentioning

confidence: 99%

Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations

et al. 2012

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“…), thyroid hormones or adrenal cortical functions (Han et al . ; Spaulding ; Leijs et al . ) among others, that could contribute to the observed impairments in SGZ NPC maturation and hippocampal function (Desouza et al .…”

Section: Discussionmentioning

confidence: 99%

Deletion or activation of the aryl hydrocarbon receptor alters adult hippocampal neurogenesis and contextual fear memory

Latchney

Hein

O’Banion

et al. 2013

Journal of Neurochemistry

102

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity of dioxin and serves multiple developmental roles. In the adult brain, while we now localize AhR mRNA to nestin-expressing neural progenitor cells in the dentate gyrus (DG) of the hippocampus, its function is unknown. This study tested the hypothesis that AhR participates in hippocampal neurogenesis and associated functions. AhR deletion and activation by the potent environmental toxicant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), adversely impacted neurogenesis and cognition. Adult AhR-deficient mice exhibited impaired hippocampal-dependent contextual fear memory while hippocampal-independent memory remained intact. AhR-deficient mice displayed reduced cell birth, decreased cell survival, and diminished neuronal differentiation in the DG. Following TCDD exposure, wild-type mice exhibited impaired hippocampal-dependent contextual memory, decreased cell birth, reduced neuronal differentiation, and fewer mature neurons in the DG. Glial differentiation and apoptosis were not altered in either TCDD-exposed or AhR-deficient mice. Finally, defects observed in TCDD-exposed mice were dependent on AhR, as TCDD had no negative effects in AhR-deficient mice. Our findings suggest that AhR should be further evaluated as a potential transcriptional regulator of hippocampal neurogenesis and function, though other sites of action may also warrant consideration. Moreover, TCDD exposure should be considered as an environmental risk factor that disrupts adult neurogenesis and potentially related memory processes.

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“…In another longitudinal study, it was shown that serum TCDD levels were correlated with serum TSH levels . It was further shown that Vietnam veterans have an up to 3.5‐times increased risk of hyperthyroidism, hypothyroidism and Grave's disease several years after initial exposure …”

Section: Discussionmentioning

confidence: 97%

“…42 It was further shown that Vietnam veterans have an up to 3.5times increased risk of hyperthyroidism, hypothyroidism and Grave's disease several years after initial exposure. 43 The tumorigenic potential of dioxins has been described in the literature, and TCDD is now classified as a human carcinogen by the International Agency for Research on Cancer (IARC) based on animal and human observational studies; in particular, non-Hodgkin lymphoma is particularly frequent. 44,45 However, this remains controversial as the evidences for a relationship between TCDD and human carcinogenesis are indirect.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 1A2 activity and incidence of thyroid disease and cancer after chronic or acute exposure to dioxins

Samer

Gloor

Rollason

et al. 2019

Basic Clin Pharma Tox

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Background Dioxin (2,3,7,8‐tetrachlorodibenzo‐p‐dioxin; TCDD) is the most toxic congener of a family of structurally and mechanistically related persistent organic pollutants whose effects are mediated through the aryl hydrocarbon receptor (AhR). Induction of CYP1A1/2 by TCDD through the AhR depends on the magnitude and the duration of exposure. We aimed to assess CYP1A2 activity after acute and chronic exposure to TCDD. The Maincy cohort is a sample population from Melun in the Val‐de‐Seine region in France that lived for at least 5 years close to a waste incinerator emitting polluted vapours (1974‐2002) with high concentrations of dioxins (up to 2000 times the maximal recommended values). Acute exposure to TCDD (Viktor Yushchenko) has been described elsewhere by Sorg et al (Toxicol. Sci. 2012; 125:310‐317). Both are rare cases of well‐identified source of chronic and acute exposure to TCDD. Methods All subjects underwent a full medical history and physical examination and had a cutaneous examination, and a retro‐auricular skin biopsy was taken. A questionnaire was designed and used regarding demographic, personal, environmental and occupational characteristics. CYP1A2 activity was assessed 2 hours after the ingestion of a drink containing caffeine through measurement of the metabolic ratio of paraxanthine (17X) over caffeine (137X) by LC‐MS/MS or LC‐UV. CYP1A1 expression in skin biopsies was determined by immunohistochemical analysis. Results Forty‐seven exposed subjects (age 11‐78) and 31 controls were included in the study. Eleven exposed subjects had a history of thyroid disease (23.4%), and 7 (14.8%) had a cancer vs none and 1, respectively, in controls. Nodular skin lesions were found in 13 exposed subjects (27.7%) vs none in controls. Mean CYP1A2 activity of the exposed population was modestly elevated as compared to controls (17X/137X metabolic ratio of 0.475 vs 0.374, P = .051). CYP1A2 was, however, induced (17X/137X, metabolic ratio >0.5) in 27.6% of the exposed cases vs 6.4% of the controls. In contrast, acute dioxin exposure was associated with a strong induction (mean 17X/137X, metabolic ratio of 1.9) still present 29 months after the acute exposure. CYP1A1 was expressed in 59.6% of the skin biopsies (highly expressed in 31.9%) of the Maincy cohort. No correlation between CYP1A2 activity, CYP1A1 expression and clinical manifestations (thyroid disease, cancer, skin lesions) could be demonstrated. Conclusion Higher frequencies of dysthyroidism and cancer were detected in the population exposed chronically to dioxins from a waste incinerator. CYP1A2 was induced in 27.6% of the exposed population, while the magnitude of induction was fourfold higher after acute exposure in the case of Yushchenko.

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The possible roles of environmental factors and the aryl hydrocarbon receptor in the prevalence of thyroid diseases in Vietnam era veterans

Cited by 24 publications

References 33 publications

Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations

Dioxin (TCDD) Induces Epigenetic Transgenerational Inheritance of Adult Onset Disease and Sperm Epimutations

Deletion or activation of the aryl hydrocarbon receptor alters adult hippocampal neurogenesis and contextual fear memory

Cytochrome P450 1A2 activity and incidence of thyroid disease and cancer after chronic or acute exposure to dioxins

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