Antibiotic induced changes to mitochondria result in potential contributions to carcinogenesis, heart pathologies, other medical conditions and ecosystem risksJorma Jyrkkanen*British Columbia, CanadaMore Information *Address for Correspondence: Jorma Jyrkkanen, British Columbia, Canada, Tel:1-250-859-5330; Email: jormabio@hotmail.com Submitted: 17 August 2020

https://www.heighpubs.org/jccm163https://doi.org/10.29328/journal.jccm.1001104Research ArticleAntibiotic induced changes to mitochondria result in potential contributions to carcinogenesis, heart pathologies, other medical conditions and ecosystem risksJorma Jyrkkanen*British Columbia, CanadaMore Information *Address for Correspondence: Jorma Jyrkkanen, British Columbia, Canada, Tel:1-250-859-5330; Email: jormabio@hotmail.com Submitted: 17 August 2020Approved: 01 October 2020Published: 02 October 2020How to cite this article:Jyrkkanen J. Antibiotic induced changes to mitochondria result in potential contributions to carcinogenesis, heart pathologies, other medical conditions and ecosystem risks. J Cardiol Cardiovasc Med. 2020; 5: 163-171. DOI: 10.29328/journal.jccm.1001104Copyright: © 2020 Jyrkkanen J. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Keywords: Antibiotic; Mitochondria; DNA damage; P53 tumor suppressor cene; Mutp53; ROS; Lipid peroxide; Cell perforation; Cell rupture; Oxidative phosphorylation; Cancer; Carcinogenesis; Glycolysis; Warburg eff ect; Microbiome; Dysbiosis; Immune suppression; Pesticides; Mechanism; Clastogenic; Epigenetic silencing; Microrna; DNA; HeartOPEN ACCESSAbstract With the discovery by Calghatgi (2013) that three common antibiotics (Abs) increased mitochondrial reactive oxygen (ROS) and lipid peroxide (LP) and depleted their natural absorbant glutathione led me to investigate further the potential impacts of these genotoxic substances on carcinogenesis. The range of impacts on mitochondria and cellular DNA varied by antibiotic to those consistent with known prior contributions to carcinogenesis. Specifi c cancers probably increased by these changes were HCC, RCC (KCC), CRC, cancer of the esophagus. Tumor suppressor gene mutations resulting from LP were noteworthy in this regard and mutations induced in CRC were consistent with those found in carcinogenesis of CRC. In addition depression of short chain fatty acids in microbiomes were found which depress the immune system increasing risk of all cancers. Many cancers were increased according to epidemiological studies linking Abs with elevated odds ratios, with one concern in particular, fatal breast cancer. The impact of loss of functionality of the mitochondria was also linked to depression of the citric acid cycle and therefore ATP which defl ected metabolism to glycolysis, the Warburg mechanism also increasing risk of all cancers, favoured by cancer cells. In conclusion, some portion of many cancer types are probably increased in likelihood by number, type and frequency of Abs treatment and chronic residue exposure which varies from individual to individual. This led me to propose a three pronged carcinogenesis mechanism for Abs. 1. Cancer critical mutations 2. Immune depression 3. loss of mitochondrial functionality leading to Warburg eff ects. Damage to mitochondria were also noted by common pesticides tested in China and cancer associations were also found for many pesticides supporting a similar contributory etiology. Heart health concerns were raised by these fi ndings because of the myriad mitochondria in the heart and because of long term reliability needs. Studies suggesting hearts were aff ected by Abs and pesticide exposure were presented. Because of their geographical ubiquitousness and the huge range of diseases associated with mitochondrial dysfunction, antibiotics and pesticides and bacteriocidal biocides are of concern for biodiversity and life in general. I propose research steps to evaluate Abs safety and suggest directions for further research and make suggestions on ways to ameliorate Abs toxicity.IntroductionAntibiotics kill or slow the growth of bacteria or interfere in their reproduction. The mitochondria, an ancient alpha-proteobacteria [Rickettseae] that has become an endosymbiont in higher life forms with critical functions, response to them has been found to be a decrease of beneβicial antioxidant glutathione, increased reactive oxygen, increased harmful lipid peroxide, possible DNA damage and mutations in tumour suppressor genes increasing cancer risk, possible inability to reproduce, possible cell perforation and or rupture. Some antibiotics have been shown in the past to be clastogenic. These types of responses have broad biochemical and health implications. They could lead to carcinogenisis, microbiome dysbiosis with resulting immune system depression and or loss of oxidative phosphorylation (OP) favouring glycolysis metabolism which is also the favoured method for cancer cells. Changes could enhance the Warburg effect favouring cancers. P53 genes may be turned off epigenetically at the DNA. Defective mitochondria have been implicated in over Antibiotic induced changes to mitochondria result in potential contributions to carcinogenesis, heart pathologies, other medical conditions and ecosystem riskshttps://www.heighpubs.org/jccm164https://doi.org/10.29328/journal.jccm.1001104200 medical conditions. In addition a big unknown is the relationship between which biocides may epigenetically shut down critical genes found with each particular kind of cancer. Clinical and epidemiological evidence supports the conclusion that some antibiotics are carcinogens, others promote cancers and cancer risk increases with frequency and type. Microbiome dysbiosis and immune depression risk is increased. While exposure may not complete all the steps to cancer it may contribute important mutations along the way. Other life time exposures can can complete the process. Chinese researchers recently found that a high proportion of common pesticides ruptured mitochondria like some antibiotics. Individuals who were exposed to pesticides were more than twice as likely overall to have conditions like heart disease, heart failure oran irregular rapid heartbeat known as atrial βibrillation [1]. It can be inferred that ruptured mitochondria from antibiotics would lead to similar coronary pathologies. There is reason to suspect that all Eukaryotes are subject to pathological impacts. The mitochondria enabled multicellular evolution to higher forms of life and is now under attack worldwide by anthropogenic biocide pollution. More research is needed to determine which of all biocides is mitochondria friendly, enables them to be fully functional without mutations, prior to regulatory approvals. I propose an antibiotic mitochondria carcinogenesis mechanism. For a general overview of impacts of antibiotics on total general physiology and health of ecosystems including plants see Wang, Xu et al. [2]. A criticism of some βindings is that people with cancer are more prone to infections and this can account for much of the association of antibiotics with cancer [3]. However the βinding of immune compromise is consistent with antibiotic induced microbiome associated dysbiosis.Mitochondrial job and creation of toxic mix by antibioticMitochondria, a primitive endosymbiotic bacteria, related to extant SARII marine bacteria and Rickettsias, in eukaryotes is responsible for OP resulting in ATP and NAD production for energy. When exposed to clinically equivalent doses of antibiotics that target bacteria (cipromycin, ampicillin, kanamycin), exhibited a decline in glutathione titre, an increase in reactive oxygen (ROS) and an increase in lipid peroxide with damage to DNA and potential mitochondrial rupture [4]. Tetracyclines used for humans and livestock have also been linked to mitochondrial genetic damage [5]. Some antibiotics have been found to be break chromosomes [6].Modes of action of antibiotics on mitochondria and microbiome1. quinolones- commonly prescribed antibacterial organoβluorine compounds which act by inhibition of bacterial DNA synthesis and result in rapid cell death [7]. This group contains oβloxacin, norβloxacin (noroxin), ciproβloxacin (Cipro), moxyβloxacin (Avelox). Expectation is to obstruct mitochondrial replication. Norβloxacin demonstrated a linear antibiotic-DNA mutation rate, compromised DNA oxidative damage repair and post replicative mismatch repair [8]. They could be expected to do similar collateral damage to mitochondria and to members of the human microbiome.2. aminoglycosides-ex gentamicin, amicasin which create holes in the outer cell wall of bacteria suggesting mitochondria and the microbiome might be at risk of similar damage [9]. Damage to lipid membranes can be expected. Lipid membranes have wide distribution in both microbes and other animals including humans.3. β-lactams or penicillin derivatives such as cephalosporins, monobactams, carbapenems, carbacephems inhibit cell wall synthesis in bacteria and by inference inhibit cell wall synthesis in mitochondria during division and repair and microbiomes thereby obstructing microbial reproduction. Penicillamine is listed as a ‘developmental’ in California Proposition 65.4. Tetracyclines-used on cattle and humans and possibly acquired secondarily as dietary residues may affect mitochondria because they speciβically target Rickettsias a probable evolutionary ancestor [2,10.11].5. Anthracyclines-result in clastogenicity [6].Harmful impact of liberated substances on DNA, P53 tumour suppressor gene, mutagenicity and known eff ects in other cancersGlutathione is an antioxidant that soaks up ROS and is essential for many neurological and other body functions. Glutathione is capable of preventing damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides, and heavy metals.Genomic instability occurs in myeloid malignancies with increased reactive oxygen species ROS, DNA double strand breaks (DSBs) and error-prone repair [12].ROS linked to many cancers by oxidative DNA damage“numerous studies have shown generation of reactive oxygen species (ROS) that can cause oxidative damage of DNA. This is a well-known mechanism in carcinogenesis for many agents” [13]. Excessive levels of ROS accumulation due to altered equilibrium between ROS and antioxidants may lead to different kinds of diseases such as atherosclerosis, diabetes, neurodegeneration, and cancer including CRC. It is widely known that ROS-induced DNA damages and genetic mutations are critical causes of cancers including CRC. The main intracellular DNA lesions caused by ROS are single and double strand DNA breaks, and the common genetic mutations include p53, KRAS, APC, and BRAF mutations often seen in CRC’s. For example, a direct relation among oxidative stress, DNA damage and elevated frequency of p53 mutation in CRC Antibiotic induced changes to mitochondria result in potential contributions to carcinogenesis, heart pathologies, other medical conditions and ecosystem riskshttps://www.heighpubs.org/jccm169https://doi.org/10.29328/journal.jccm.1001104Follow up researchTo resolve the safety of antibiotics (Abs) regarding their potential impact on mitochondrial impacts, I have arrived a number of research questions which can help steer our understanding and antibiotic futures. Independent academic institutional involvement is preferred so that vested interestsdon’t cloud the results.1. How large and persistent is the glutathione decrease, ROS and lipid peroxide increase post antibiotic treatment for each antibiotic if any?2. What effect do Abs have on future reproduction, integrity and populations of mitochondria in heart muscle.3. Need to survey and list genetic mutations and epigenetic alteration of cancer gene expression and especially cancer gene silencing post Abs treatment in DNA and microRNA.4. Assess dysbiosis linked impacts on immune system post Abs treatment and duration of the effect.5. Do a full analysis of coronary function and mitochondrial health post Abs for each Abs.6. Broad survey of Abs clastogenicity with complete description.7. Which Abs rupture mitochondria and or cells and at what concentrations?8. Assay 8-oxodG post Abs treatment to determine potential carcinogenicity?9. Do any Abs impact on promotion of hepatocellular carcinoma and CRC?10. Assay tumor suppressor epigenetic gene up-regulation, down-regulation, silencings and mutations and their loci for P53 and TUSC and TpMs.11. Conduct a population study for Abs usage and Breast Cancer with proper controls and examine BC associated genes [55] for mutations or epigenetic silencings post Abs treatments and relationship to exposure history.12. Assess OP and glycolysis potential of each Abs to determine potential for Warburg effect.13. Abs history study of HPV oropharyngeal cancers in men in developed countries.14. Abs impact on proteasome activity.15. Assay Abs for reverse Warburg activity for H1F(alpha) and FOS-JUN which stimulate cancer cell proliferation.16. Assay Abs treatment for caveolin 1 in adjacent stromal βibroblasts which increase mitophagy and lactate in βibroblastsdriving tumor growth and proliferation.17. Routine clinical assay for interstitial ATP titre recovery once antibiotic use is discontinued to see if the Warburg effect if initiated on application has been neutralized.I think this would clarify the scale and degree of impact of antibiotics and point to areas needing remedies. Many other diseases are linked to mitochondrial alterations. The reader is referred to Salvatore diMauro and Darryl C De Vivo book Diseases of Mitochondrial Metabolism. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Siegel GJ, Agranoff BW, Albers RW, et al. [39], editors. Philadelphia:Lippincott-Raven; 1999. Salvatore diMauro and Darryl C De Vivo.The most urgent in the light of growing antibiotic resistance are these two critical health questions, ie mitochondrial health relative to heart health and carcinogenicity contributions.References1. Lisa Rapaport. 2019. Health News January 9, 2019 / 3:30 PM/Reuters.2. Wang X, Dongreol R, Johan A. 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Published online 2019 Aug 14. doi: 10.3390/cancers11081174 PMCID: PMC6721461 PMID: 31416208 Use of Antibiotics and Risk of Cancer: A Systematic Review and Meta-Analysis of Observational Studies Fausto Petrelli,1,* Michele Ghidini,2 Antonio Ghidini,3 Gianluca Perego,4 Mary Cabiddu,1 Shelize Khakoo,5 Emanuela Oggionni,6 Chiara Abeni,7 Jens Claus Hahne,8 Gianluca Tomasello,9 and Alberto Zaniboni7 Author information Article notes Copyright and License information Disclaimer This article has been cited by other articles in PMC. Go to: Abstract The association between antibiotic use and risk of cancer development is unclear, and clinical trials are lacking. We performed a systematic review and meta-analysis of observational studies to assess the association between antibiotic use and risk of cancer. PubMed, the Cochrane Library and EMBASE were searched from inception to 24 February 2019 for studies reporting antibiotic use and subsequent risk of cancer. We included observational studies of adult subjects with previous exposure to antibiotics and available information on incident cancer diagnoses. For each of the eligible studies, data were collected by three reviewers. Risk of cancer was pooled to provide an adjusted odds ratio (OR) with a 95% confidence interval (CI). The primary outcome was the risk of developing cancer in ever versus non-antibiotic users. Cancer risk’s association with antibiotic intake was evaluated among 7,947,270 participants (n = 25 studies). Overall, antibiotic use was an independent risk factor for cancer occurrence (OR 1.18, 95%CI 1.12–1.24, p < 0.001). The risk was especially increased for lung cancer (OR 1.29, 95%CI 1.03–1.61, p = 0.02), lymphomas (OR 1.31, 95%CI 1.13–1.51, p < 0.001), pancreatic cancer (OR 1.28, 95%CI 1.04–1.57, p = 0.019), renal cell carcinoma (OR 1.28, 95%CI 1.1–1.5, p = 0.001), and multiple myeloma (OR 1.36, 95%CI 1.18–1.56, p < 0.001). There is moderate evidence that excessive or prolonged use of antibiotics during a person’s life is associated with slight increased risk of various cancers. The message is potentially important for public health policies because minimizing improper antibiotic use within a program of antibiotic stewardship could also reduce cancer incidence. Keywords: cancer, antibiotics, meta-analysis, risk factor