First Let Me Tell You > > > I Am Not A Scientist

1. First Let Me Tell You > > >I Am Not A Scientist

2. Just a old Veteran who went to war as young man.

3. Part One • Neurodegenerative Diseases: Parkinson’s Disease - Atypical Parkinsonism - Oxidative Stress – Protein Misfolding

4. Our Key Points

5. Our Key Points 1. There are new studies supporting the association between not only Parkinson’s disease but also parkinsonism and “Agent Orange”

6. Our Key Points 2. There are common paths in the development of parkinsonian diseases and other neurological conditions: • Oxidative stress • Misfolding of proteins • Loss of brain cells.

7. Our Key Points 3. There is a shared common molecular mechanism between oxidant and specific neurotoxins. 4. In studies, “Agent Orange” herbicides and dioxin create oxidative damage in neuron cells.

8. Our Key Points 5. TCDD dioxin may directly regulate the dopamine system. 6. The common paths and shared mechanism apply to the rare parkinsonism diseases, each affecting less than 20,000 people in the U.S..

9. Our Input

10. Our Input • A study (Tanner et al., 2009) examined the risk of parkinsonism in occupation and toxic exposures and found a 2.59 increased risk in parkinsonism with exposure to 2,4-D, a herbicide agent in “Agent Orange”. (36)

11. Our Input • A study (Willis et al., 2010) looked at residential environmental risks in conjugal parkinsonism and PD with 17 of the 18 subjects reporting at least one of the environmental exposure of interest. (37)

12. Our Input • A study (DonggunSul, 2008) showed that “TCDD exposure induces neurotoxicity in N2a cells by increasing DNA damage, oxidative stress and intracellular calcium levels. The TCDD-mediated increase of tau phosphorylation in particular indicates an important role for tau hyperphosphorylation in TCDD-induced neurotoxicity.” (15) 

13. TCDD Dioxin

14. TCDD Dioxin

15. Our Input • “Agent Orange” herbicides and dioxin have been shown to produce this type of damage in neuron cells. (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29)

16. Our Input • Atypical Parkinsonism include progressive supranuclear palsy (PSP), multiple systems athrophy (MSA), cortialbasal degeneration (CBD) and dementia with Lewy bodies (DLB). Common to these disease along with Parkinson’s disease (PD) are the loss of neuron cells, the misfolding of various proteins and damage from oxidative stress. (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) 

17. Our Input • There is a shared common molecular mechanism between oxidant and neurotoxins. (30)

18. Our Input • Protein misfolding of the alpha-synuclein and tau proteins are shared across a lot of the neurodegenerative disease. Tau aggregations are found in PD as well as parkinsonism and other neurodegenerative diseases. (32) (33) (34) (35)

19. Our Input • Genes found to be associated with Parkinson’s disease are related to alpha-synuclein protein, dissolving proteins, or the antioxidant response to oxidative stress. These are the same processes associated with toxic exposures.

20. Our Concerns

21. Our Concerns • Atypical Parkinsonism (PSP, MSA and CBD) are rare diseases with a prevalence of between 3 to 7 in 100,000. Due to the small number of Vietnam Veterans with these diseases it will be unlikely that they show up in epidemiological studies, making it important that any evidence of association be weighed with due consideration.

22. Our Concerns • As each of you know the real world of a military troop is not a laboratory and that the real story of toxin exposures are not isolated incidents. While the charge of this committee is to look at the herbicides deployed tactically and their components, we have concerns that the past committees have not strongly voiced that toxins and mixtures of toxins not looked at by this committee may be behind some of the health issues facing Vietnam Veterans.

23. Our Concerns • Many veterans are dying waiting on the association between diseases and their chemical exposures. The lack of research and the slowness of the administrative process is shameful. A number of members from our group have passed away since this committee’s last update was published last in July (2009). They and their families suffered without the care and help that would have made their lives easier. The stress of the claims process and waiting certainly sped the progression of their disease and their demise. This is why your work is so important.

24. Our Requests

25. Our Requests • That this committee review the current literature related to oxidative stress, protein misfolding and cell loss as well as shared pathways and common molecular mechanism in regards to neurodegenerative diseases and especially parkinsonian diseases.

26. Our Requests • That the committee take into consideration the rarity of these diseases in reviewing the available evidence

27. Our Requests • That the committee elevate the association of Parkinson’s disease from limited/suggestive association to adequate evidence of association to “Agent Orange”.

28. Our Requests • In view of the recent findings of the association of ALS with military service and PD with “Agent Orange” we request the committee take an individual look at all neurodegenerative disease in this and future updates.

29. Our Requests • That at the start of each review period, you request from the DVA the actions taken on the recommendations made by the committee in the previous Veterans and Agent Orange Review and updates. It seems appropriate for this committee to report in each following update , the progress or lack of progress made on the previous recommendations.

30. Our Requests • That you strongly voice the fact that Vietnam veterans were exposed to toxins that are not considered by the committee and that these veterans may be suffering with illness associated with these other toxins or due to the mixture of the herbicides and other chemicals.

31. Our Children & Future Generations

32. Second Part TCDD, Oxidative Stress, Sperm, DNA Damage, Birth Defects

33. Our Points

34. Our Points • 1. “Agent Orange” dioxin, TCDD can create DNA damage in the sperm through oxidative stress. • 2. The DNA damaged sperm can result in conception. • 3. The altered paternal damaged DNA can be passed to the conceptus.

35. Our Points • 4. The damage paternal DNA can result in birth defects and illnesses in the offspring. • 5. The possibility that repair attempts of the paternal altered DNA in early embryo development may lead to changes in the male nucleus structure and transgenerational information as well. • 6. That paternal epigenetic transmission can take place in the pre-S-phase zygotes.

36. Our Input

37. Our Input • We browsed the past Veterans and Agent Orange Review and Updates and found no indication that the previous committees have looked at the role of toxic induced oxidative stress in creating DNA damage in sperm and the potential adverse reproductive outcomes.

38. Our Input • In animal studies many toxins impact the epididymal sperm and cause DNA damage in a similar fashion, through oxidative stress (1) (2) (3) (4) (5) (16). This includes TCDD, the dioxin in “Agent Orange” (6) (7) (13) (18). Other studies and reviews point out that fertilization and implantation do occur with DNA damaged sperm. (8) (9).

39. Our Input • When implantation does occur, the altered defective paternal DNA can be passed on to the conceptus. (9) (10). Damaged sperm DNA can influence the time to pregnancy (12). When passed on, altered DNA can result in adverse outcomes for the offspring including birth defects and childhood cancers (14) (15).

40. Our Input • During the early embryo development in the cleavage stage S-phase any attempts to repair the paternal altered DNA may change the male nucleus structure and the transgenerational information as well (17).

41. Our Input • One study we found present evidence of paternal epigenetic transmission taking place prior to the stage S-phase in the embryo development. “…demonstration of paternal histones in pre-S-phase pronuclear human zygotes and zygotes produced by human sperm and mouse oocytes. This could have consequences for early developmental processes via enabling downstream effects of sperm derived nucleosomal chromatin that contains variants and/or carries histone modifications. A higher nucleosomal content in sperm as is now found in human oligospermia would then lead to expanded epigenetic transmission.” (19)

42. Our Concerns

43. Our Concerns • That the above studies, viewed as a group, present reasonable concern for veterans to believe that the birth defect and illnesses found in their children and grandchildren are a result of the veterans’ own exposure to TCDD dioxin during military service

44. Our Concerns • Also, it appears that environmental induced oxidative stress on the sperm could cause damage anywhere along the DNA strand. This may create a variety of adverse impacts on the offspring. The results could be a cluster of varied birth defect in an exposed group where clusters of individual birth defects may not be detectable at a significant level.

45. Our Concerns • We are also concerned with the lack of research devoted to the impact of toxic exposure on the offspring of veterans and especially Vietnam veterans.

46. Our Request

47. Our RequestsThat this committee: • Review the scientific evidence available on the ability of toxic exposures, especially TCDD, to create sperm DNA damage and pass the altered DNA to the offspring that could result in adverse reproductive outcomes or impacts. • Review the data available in the Ranch Hand studies to see if there is an increase in the risk for all birth defects in general for these veterans.

48. Our RequestsThat this committee: • Make recommendations to the Secretary of the Department of Veterans Affairs (DVA) on studies for the adverse reproductive outcomes caused by altered sperm DNA.

49. Our RequestsThat this committee: • A new study, (Carlos Guerrero-Bosagna Sep 2010) “confirms that an environmental agent has the ability to induce epigenetic transgenerational changes in the sperm epigenome.” • The study investigates “genome-wide promoter DNA methylation alterations in the sperm of F3 generation rats whose F0 generation mother was exposed to vinclozolin.”

50. Thank You!!