How Breathing Heptachlor / Chlordane Ages Your Brain / A Unifying Mechanism of Neurodegeneration

Experts now agree that oxidants (free radicals) are a major risk factor for neurodegenerative diseases (Parkinson’s (1,2 – see References below), Alzheimer’s (3,4), Huntington’s (5), and Amyotrophic Lateral Sclerosis (Lou Gehrig) diseases) (6), cognitive decline (7), and depression (8). Antioxidants neutralize oxidants and various cellular mechanisms repair oxidized DNA and other macromolecules in the neuron.  Over a person’s lifespan these events can be summarized by the following equation:

Neurodegeneration = oxidant (free radicals) production – oxidants neutralization by antioxidants – repair of oxidized DNA and cellular components

A recent research review entitled “A Unifying Mechanism of Neurodegeneration” (9) shows how altered genes, which normally produce the DNA repair proteins, allow early onset of neurodegenerative diseases.  Insufficient repair of DNA single strand breaks by defective repair proteins in these families, leads to early-onset movement disorders (10, 11).

Reduced exposure to environmental agents which cause immune cells to produce oxidants would be beneficial to all, but especially valuable to persons having incomplete DNA repair machinery.  My research (12) has shown the heptachlor epoxide, a stable metabolite of heptachlor, at levels found in the blood of Americans (13), can induce human immune cells to produce the oxidant nitric oxide that causes single strand breaks in DNA.  Likewise, heptachlor epoxide would induce microglia, the immune cell of the brain, to produce nitric oxide that then diffuses though cell membranes (14,15) and damages DNA of surrounding neurons.

Furthermore, my research (12) indicated heptachlor epoxide induced-neuronal damage would be exacerbated by inflammatory processes (i.e., presence of inflammatory mediators such as Tumor Necrosis Factor alpha) resulting in a greater breadth and depth of nitric oxide production and DNA damage in surrounding neurons.

Heptachlor is the most potent toxicant of the four major components of technical chlordane (heptachlor, cis-chlordane, trans-chlordane, trans-nonachlor). Technical chlordane was used as an insecticide in agriculture from the 1950’s until being banned in 1976.  More significant to human health, technical chlordane was also used for the prevention/treatment of termite infestation in U.S. homes until being banned in1988.  U.S. Environmental Protection Agency (USEPA) estimated that over 30 million homes were treated with technical chlordane. The level of heptachlor, cis-chlordane and  trans-chlordane in the indoor air of these homes increased markedly, if technical chlordane was applied to the soil under the basement floor, concrete slab, or crawl space, compared to only the soil surrounding the home’s foundation.

Since 1996, I have been sampling and analyzing the concentrations of heptachlor, cis-chlordane, trans-chlordane, and aldrin in indoor air of homes in the U.S.  I continue to find high levels of heptachlor and cis- and trans-chlordane in the indoor air of homes, especially those with treatment under the home (16). The Non-Occupational Pesticide Exposure Study (NOPES) conducted by the USEPA established that the main route of exposure to heptachlor and chlordane was by inhalation of indoor air of treated homes.  Heptachlor daily intake in Americans was 7-13 times higher via inhalation than via ingestion of food (17).

Since oxidants (free radicals) are risk factors for various neurodegenerative diseases, and since chlordane / heptachlor, at concentrations found in American’s blood, increase oxidants production in human immune cells that damage surrounding cells (neurons), then inhabitants of contaminated homes breathing high levels of chlordane / heptachlor would have increased risk for neurodegenerative diseases. Recent research indicates that Americans with higher levels of chlordane, heptachlor or their metabolites (heptachlor epoxides or oxychlordane) in their blood have increased risk for Parkinson’s Disease (18,19), Amyotrophic Lateral Sclerosis (20), cognitive decline (21,22) and depression (23,24).

REFERENCES:

1. Blesa, J, et al., (2015). Oxidative stress and Parkinson’s disease. Front. Neuroanat. 9:1-9. http://journal.frontiersin.org/article/10.3389/fnana.2015.00091/full                                                                                                                         
2. Dias, Vera, et al. (2013). The Role of Oxidative Stress in Parkinson’s Disease. J. Parkinsons Dis. 3:461–491. http://content.iospress.com/download/journal-of-parkinsons-disease/jpd130230?id=journal-of-parkinsons-disease%2Fjpd130230

1. Migliore, L. et al. (2005). Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiology of Aging.26-567-773. http://dx.doi.org/10.1016/j.neurobiolaging.2004.07.016/                                                                                                      
2. Lovell, Mark A. et al. (1999). Increased DNA Oxidation and Decreased Levels of Repair Products in Alzheimer’s Disease Ventricular CSF. J. Neurochem. 72:771–776. http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.1999.0720771.x/full/

5. Haun, F. et al. (2013). S-nitrosylation of dynamin-related protein 1 mediates mutant huntingtin-induced mitochondrial fragmentation and neuronal injury in Huntington’s disease. Antioxid. Redox. Signal. 19:1173-84. http://online.liebertpub.com/doi/abs/10.1089/ars.2012.4928

6. Coppedè, Fabio. (2011). An Overview of DNA Repair in Amyotrophic Lateral Sclerosis. TheScientificWorldJOURNAL. 11:1679–1691. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201689/pdf/TSWJ11-853474.pdf                                                                                              
7. von Bernhardi, R. et al. (2015). Microglial cell dysregulation in brain aging and neurodegeneration. Front. Aging Neurosci. 7:1-21. http://journal.frontiersin.org/article/10.3389/fnagi.2015.00124/full

8. Black, C. N. et al. (2016). Oxidative stress, anti-oxidants and the cross-sectional and longitudinal association with depressive symptoms: results from the CARDIA study. Translational Psychiatry. 6, e743; http://www.nature.com/tp/journal/v6/n2/pdf/tp20165a.pdf 

9. Ross, Christopher A. and Truant, R. (2017). A Unifying Mechanism in Neurodegeneration. Nature. 541:34. https://www.researchgate.net/publication/311821137_DNA_repair_A_unifying_mechanism_in_neurodegeneration                                 
10. Hoch, Nicholas C. et al. (2017). XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature. 541:87-91. http://www.nature.com/nature/journal/v541/n7635/full/nature20790.html                                                                                                             
11. Islam M. T.  (2017). Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurol. Res. 39:73-82. https://www.researchgate.net/profile/Mohammed_Islam16/publication/309196188_Oxidative_stress_and_mitochondrial_dysfunction-linked_neurodegenerative_disorders/links/581c62cf08aea429b291b65b.pdf                                                                                                     
12. Cassidy, Richard A. et al. (2005). The link between the insecticide heptachlor epoxide, estradiol, and breast cancer. Breast Cancer Research and Treatment. 90:55–64. http://toxfree.net/chlordane/Cassidy/cassidypdf/BreastCancer.pdf                                                          
13. Fourth National Report on Human Exposure to Environmental Chemicals (2009). Centers for Disease Control and Prevention. Atlanta, GA 30341-3724. Website: http://www.cdc.gov/exposurereport.

14. Cassidy, Richard A. et al. (2000). Effects of heme proteins on nitric oxide levels and cell viability in isolated PMNs: a mechanism of toxicity. Journal of Leukocyte Biology.  67:357-68. PMID: 10733096. www.dtic.mil/cgi-bin/GetTRDoc?AD=ADA628397                             
15. von Bernhardi, R. et al. (2015). Microglial cell dysregulation in brain aging and neurodegeneration. Front. Aging Neurosci. 7:1-21.  http://journal.frontiersin.org/article/10.3389/fnagi.2015.00124/full

16. http://toxfree.net/chlordane/Cassidy/levels_graph.php                                                                                                                                                  
17. Whitmore, R. W. et al., (1994). Non-Occupational Exposures to Pesticides for Residents of Two U.S. Cities. Arch. Environ. Contain. Toxicol. 26:47-59. http://nchh.org/Portals/0/Contents/Article0283.pdf                                                                                                                     
18. Abbott, Robert D. et al. (2016). Midlife milk consumption and substantia nigra neuron density at death. Neurology. 86:512–519. http://www.neurology.org/content/86/6/512                                                                                                                                                                      
19. Ross, G. Webster. et al. (2012). Brain organochlorines and Lewy Pathology: The Honolulu-Asia Aging Study. Mov Disord. 27:1418–1424. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474594/pdf/nihms395184.pdf                                                                                       
20. Su, Feng-Chiao. et al. (2016). Association of environmental toxins with amyotrophic lateral sclerosis. JAMA Neurol. 73:803-811. http://jamanetwork.com/journals/jamaneurology/fullarticle/2519875                                                                                                                        
21. Lee, Duk-Hee et al. (2007). Association of serum concentrations of persistent organic pollutants with the prevalence of learning disability and attention deficit disorder. J. Epidemiol. Community Health. 61:591–596. http://dx.doi.org/10.1136/jech.2006.054700      
22. Kim, Se-A. et al. (2015). Greater cognitive decline with aging among elders with high serum concentrations of organochlorine pesticides. PLOS ONE. 10:1-9.  http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0130623&type=printable                 
23. Kilburn, K. H. and Thornton, J. C. (1995). Protracted neurotoxicity from chlordanesprayed to kill termites. Environ. Health Perspect. 103:690-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1522193/pdf/envhper00356-0059.pdf

24. Kilburn, K. H.^, (1997). Chlordane as a neurotoxin in humans. South Med. J. 90:299-304    https://www.ncbi.nlm.nih.gov/pubmed/9076301