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Taking the Driver’s Seat in your Diagnosis

By: Mari Hoffman, Genetics and Genomics 2021 

Author’s Note: In this paper, I will be discussing reviews on patient activation level and health outcomes in chronic diseases. I wanted to analyze the effect patients can have on their own treatment plans and discuss how they can make a difference. I feel personally connected to this topic because my dad was diagnosed with chronic lymphocytic leukemia and has been a role model for me in his journey of his treatment plan.  

 

Patient involvement and education in their diagnosis is not a novel idea, but has been shown to play a role in overall patient experience [1, 2]. Chronic illnesses create responsibilities and demands on patients to manage and understand their care and diagnosis. It has been shown that chronic disease patients who take on a bigger role and engagement level with their own health have more positive outcomes [3]. Patient engagement or patient activation can be defined as “the individual’s knowledge, skill, and confidence for managing their own health” [3].

Patients who are more involved in their diagnosis and treatment have been shown to have more positive outcomes. One study used survey data from cancer patients and assessed how patient activation level affected actions taken on by the patient, communication with the doctor, and overall satisfaction with their care and treatment [3]. The study used survey data that was collected by CancerCare who sent out six different online surveys to cancer patients in order to test their patient activation measure [3]. The survey was sent out to a sample that consisted of those who were 25 years or older and had received a cancer diagnosis [3]. The study population varied in different characteristics and after controlling for demographics and health status factors, the study found that patients who scored higher in their activation level were 4.7 times more likely to start exercise and 3.3 times more likely to start a healthier diet when compared to patients who scored less in their activation level [3]. The study also found that less activated patients had a lower score in following their doctor’s recommendations, discussing side effects with their doctor, and in their overall satisfaction of their care received [3]. As discussed above, patients who scored higher on their activation level are more likely to be better informed on their treatment options and have greater proactivity in managing their condition [3].

There are a wide range of different factors that have been found to affect a patient’s interest in participating in their health care decision-making. These factors are related to demographic, personal characteristics, ability to put time in, stage and severity of disease, and the influence from the practitioner [4]. There are many reasons not stated above why one may or may not involve themself in their own treatment decisions and plans. 

Information about one’s diagnosis and care treatment is one of the ways in which a patient can educate themself. This information enables people to understand and exchange with their healthcare provider on consequential decisions [4]. Education of the disease has been shown to increase the patient’s willingness to ask questions because they are more confident in their understanding and therefore participate in a more active role in their treatment plan [4]. Decreasing the gap in education on their diagnosis also leads patients to better understand their own personal requirements with regard to their treatment and personalized treatment in terms of exercise and diet, and trust in their doctor to take their recommendations [4]. 

Patient education and proactiveness can even lead to a patient becoming a driver in their own diagnosis. In January of 2016, my dad was diagnosed with chronic lymphocytic leukemia by a general hematologist and was put on a “watch and wait” approach. This approach essentially means that a patient’s condition is monitored without receiving any treatment until there is a change in symptoms [5]. This made sense for my dad since his cancer was slow moving and he did not have many symptoms. Around six months later, the hematologist said he needed to be treated with fludarabine, cyclophosphamide, and rituximab (FCR), which is a Cytotoxic Chemotherapy. The doctor gave no real explanation for why he had to be treated at that time and regarding FCR, he simply said “it’s the gold standard.” At this time, my dad had started to get connected with CLL support groups such as the CLL Society and decided to get a second opinion. Through the process of educating himself and receiving a second opinion, he realized there were many negative side effects that came with FCR that his doctor did not inform him about, and he would need his genetics tested to even see if he was compatible with the treatment. When he brought up his genetics to the doctor, the doctor responded saying he thought they already did that. My dad left the appointment feeling shocked and realizing he needed to be informed and educated on his treatment options if he wanted the best possible treatment. After doing genetic testing, he found over 50% of his cells were 17P deleted and he also had Trisomy 12. This meant his genetics would not be compatible with the treatment plan. It was becoming apparent to my dad that new non-cytotoxic treatments were superior for most CLL patients. He decided to take the initiative to continue to “watch and wait” and explore other options. 

After a couple of months, his symptoms started to progress and he got an appointment with a doctor at University of California, San Diego (UCSD) who told him that there was a clinical trial happening that could be a potential treatment option for his disease. Through his own research and the resources he found through the CLL Society website, support groups, and UCSD, he decided this was the right treatment for him. It was good that he chose to wait rather than take the initial treatment offered; if he chose the latter, he would have not qualified for the trial. He has been on the clinical trial with Venetoclax and Ibrutinib for about two years now and has shown normal numbers in terms of his white blood count, which is used to measure the presence of CLL. Through the resources provided to him, he was able to gain knowledge and connections with experts in the field to feel confident in his decision to find a treatment plan that worked for him. My dad is now very involved with the CLL Society and founded a local CLL support group in San Diego where they meet to discuss their experiences and bring in health professionals to lead discussions. 

My dad’s personal story and the data shown above shows how imperative it is to do research and educate yourself on your own condition. It is critical to get your main information and opinions from your doctor, and to always consider a second opinion. Evidently, educating yourself on your own health and treatment plans can have beneficial effects overall, but it is critical to remember that doctors and health care professionals are trained in their field. It is very important to use your education and resources to find a specialist in your disease and start a conversation with them. Although you may not have all the resources in the beginning, the best advocate for your health and future is yourself. Use all the resources you can to continue to be informed and in touch with the professionals in the study of your disease. 

 

References: 

  1. Thompson, Andrew G.h. “The Meaning of Patient Involvement and Participation in Health Care Consultations: A Taxonomy.” Social Science & Medicine, vol. 64, no. 6, 2007, pp. 1297–1310., doi:10.1016/j.socscimed.2006.11.002.
  2. Hibbard, Judith H., and Jessica Greene. “What The Evidence Shows About Patient Activation: Better Health Outcomes And Care Experiences; Fewer Data On Costs.” Health Affairs, vol. 32, no. 2, 2013, pp. 207–214., doi:10.1377/hlthaff.2012.1061.
  3. Hibbard, Judith H., et al. “Does Patient Activation Level Affect the Cancer Patient Journey?” Patient Education and Counseling, vol. 100, no. 7, 2017, pp. 1276–1279., doi:10.1016/j.pec.2017.03.019.
  4. Vahdat, Shaghayegh et al. “Patient involvement in health care decision making: a review.” Iranian Red Crescent medical journal vol. 16,1 (2014): e12454. doi:10.5812/ircmj.12454

Idiopathic Pulmonary Fibrosis (IPF): PHMG-P and Other Disinfectant-associated Chemicals as Potential Causes, the Mechanism, and Potential Treatments

By Téa Schepper, Biological Sciences ‘19

Author’s Note
I would like to give special thanks to Professor Katherine Gossett (UC Davis) for encouraging me to write this paper and Dr. Angela Haczku (UC Davis Health) for her expertise in pulmonary diseases. Last fall, I decided to research idiopathic pulmonary fibrosis after my grandfather was hospitalized and diagnosed with it over the previous summer. I quickly discovered that there wasn’t much research on the disease itself or how to treat it due to its rarity. The purpose of this literature review is to inform others about idiopathic pulmonary fibrosis and to encourage further research on the subject. With time, this research could be vital in saving lives just like that of my grandfather.

Abstract
Idiopathic pulmonary fibrosis (IPF) is an irreversible and fatal disease of the lungs. Although it has been associated with genetic predisposition, cigarette smoking, environmental factors (e.g. occupational exposure to gases, smoke, chemicals, or dusts) and other conditions such as gastroesophageal reflux disease (GERD), the mechanism and causes of IPF are not yet fully understood by researchers. However, recent studies have provided evidence that IPF may be caused by the generation of reactive oxygen species (ROS) due to the inhalation of chemicals commonly found in household disinfectants. These chemicals have been identified as polymethylene guanidine phosphate (PHMG-P), didecyldimethylammonium chloride (DDAC), polyhexamethylene biguanide (PHMB), oligo(2-(2-ethoxy)-ethoxyethyl) guanidinium chloride (PGH), and a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT). It has been suggested that the generation of ROS by these chemicals is responsible for damaging the cellular structures of the lungs and triggering the development of IPF through the activation of the transforming growth factor β (TGF-β) signaling pathway. Studies have also shown microRNAs to be key regulators of the TGF-β pathway and the development of the disease. Several promising future treatments of IPF involve the inhibition of the TGF-ꞵ signaling pathway either through the administration of drugs containing sesquiterpene lactones, matrine, or oridonin compounds; or through the replenishment or inhibition of certain miRNAs. The studies detailed here highlight the importance of further research on IPF.
Keywords: idiopathic pulmonary fibrosis | PHMG-P | TGFβ | miRNA

Introduction
Pulmonary fibrosis is an irreversible, fatal disease that results in scarring of the lung tissue and decreased function of the lungs. Idiopathic pulmonary fibrosis simply means that the cause is unknown. Patients with IPF typically experience difficulty breathing, with death caused by either respiratory failure or incurrent pneumonia. [1] The disease is characterized by marked collagen deposition and other alterations to the extracellular matrix (ECM), a network of macromolecules that provide structural support to the lungs. [1] These alterations to the ECM remodel and stiffen the lung’s airspaces and tissues. [1] It is also characterized by diffuse interstitial inflammation and respiratory dysfunction. [2] Although its cause remains unknown, it is believed that the main steps in the pathogenesis of IPF are initiated by the transforming growth factor β (TGF-ꞵ) signaling pathway and involves the migration, proliferation, and activation of lung fibroblasts and their differentiation into myofibroblasts. [3] Fibroblasts are cells that have a high ability to proliferate and to produce ECM and fibrogenic cytokines. [3] Fibrogenic cytokines are multifunctional immunoregulatory proteins that contribute to the inflammatory cell recruitment and activation needed to promote the development of fibrosis. [4] These cytokines can activate myofibroblasts, which are primarily responsible for the synthesis and excessive accumulation of ECM components, collagen and fibronectin, during the repair process that leads to fibrosis. [5], [6]

A 2011 outbreak of pulmonary fibrosis in South Korea prompted an onslaught of research as to how IPF may be caused and treated. [7] Specifically, this research has provided evidence that certain chemicals commonly found in household disinfectants can cause IPF through the generation of reactive oxygen species (ROS). ROS have a powerful oxidizing capability that can induce the destruction of cellular and subcellular structures in the lung, including DNA, proteins, lipids, cell membranes, and mitochondria. [8] This damage caused by ROS has been found to promote the activation of the TGF-ꞵ signaling pathway and the development of numerous characteristics associated with IPF. [4] This research has been invaluable for the discovery of new potential treatments for patients with IPF.

Potential inducers of idiopathic pulmonary fibrosis
After the 2011 outbreak in South Korea, researchers were able to find a connection between IPF and exposure to chemicals commonly found in household disinfectants, such as those found in humidifiers and pools. They have suspected that these chemicals can cause pulmonary fibrosis by infiltrating the respiratory system as aerosol particles to induce cellular damage. The chemicals polymethylene guanidine phosphate (PHMG-P), didecyldimethylammonium chloride (DDAC), polyhexamethylene biguanide (PHMB), oligo (2-(2-ethoxy) ethoxyethyl guanidinium chloride (PGH), and the mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) attracted particular interest.

In a study evaluating registered lung disease cases in South Korea, it was revealed that 70 percent of registered patients that suffered from IPF or other forms of household humidifier disinfectant-associated lung injury had used humidifier disinfectants containing the chemicals PHMG, PGH, or a mix of CMIT and MIT prior to their development of the disease [7] It was determined that the aerosol water droplets emitted by the humidifiers may have acted as carriers to deliver these chemicals into the lower part of the respiratory system, causing humidifier disinfectant-associated lung injury. [7] It was also revealed that most of the affected patients in the study had used humidifier disinfectant containing the chemical PHMG. [7]

Another study detailed that even slight exposure to PHMG could cause cell death triggered by the generation of reactive oxygen species (ROS). [8] Injury by ROS is typically followed by a fibrotic repair process involving increases in TGF-ꞵ expression, increased fibronectin, collagen synthesis, and a marked increase in the deposition of the ECM, all key characteristics of IPF. [4]

One way that ROS promote ECM deposition and IPF is by activating transcription factors like nuclear factor kappa B (NF-κB). [4] NF-κB is a regulator of proinflammatory cytokines that is typically bound to a cytoplasmic inhibitor. [9] One study found that exposure to the biocide (substance that destroys/prevents growth in organisms) and preservative PHMB was able to generate significant ROS levels and activate the NF-κB signaling pathway through the degradation of its inhibitor. [10] This is significant because the activation of proinflammatory cytokines is necessary for the recruitment and activation of myofibroblasts responsible for the increased ECM deposition that is characteristic of IPF patients. PHMB is also a cationic chemical and there is evidence that it can bind to negatively charged mucins, located within the mucous membranes of various organs. This can cause organs located in the respiratory tract to acquire increased susceptibility to PHMB and, in effect, a higher likelihood for the development of IPF. [10] Although the study did not match the exposure conditions of PHMB in humans, it has illuminated another way that individuals may develop IPF. [10]

In a study investigating the role of DDAC—one of the aerosols— in causing pulmonary fibrosis, mice exposed to DDAC exhibited fibrotic lesions that increased in severity over time. [11] Exposure to the chemical DDAC increased TGF-β signaling and appeared to maintain the differentiation of myofibroblasts. [11] This was complemented by the high expression of genes responsible for the production of collagen in fibrogenic lungs. [11] Overall, the form of pulmonary fibrosis that was induced by DDAC was mild, and so more research must be conducted before it can be concluded that the chemical DDAC is responsible for irreversible, severe pulmonary fibrosis. [11] It is also possible that some of the patients affected with humidifier disinfectant-associated lung injury may have experienced synergistic or additive effects from using multiple humidifier disinfectants, but this can be difficult to determine. [7] However, this study does indicate that exposure to DDAC can result in the development of several characteristics typically associated with IPF.

PHMG-P as a potential causative of IPF
Of the chemicals listed in this literature review, PHMG-P has received the most attention by researchers. PHMG-P is a biocide that exhibits its antibacterial effect by disrupting the cell wall and inner membrane of bacteria, causing cellular leakage. [12] In a similar manner, PHMG-P can infiltrate the lungs in the form of aerosol particles and may cause IPF in individuals through the generation of ROS and the disruption of the ECM’s alveolar basement membrane. [4]

Disruption of the basement membrane occurs through increased expression of matrix metalloproteinases (MMPs), enzymes that degrade various components of connective tissue matrices. [6] Metalloproteinase MMP2, in particular, destroys the basement membrane by solubilizing ECM elastin, fibronectin, and collagen, helping immune cells and fibroblasts migrate to alveolar spaces. [12] This can lead to severe damage of the lung architecture and aberrant ECM deposition typical of IPF. [4]

In a study using an air-liquid interface (ALI) co-culture model to study the pathogenesis of fibrosis, PHMG-P was shown to trigger ROS generation, airway barrier injury, and inflammatory response. [4] Recall that exposure to other chemicals suspected of being potential inducers of IPF had similar effects. Therefore, it can be concluded that PHMG-P infiltrates the lungs in the form of aerosol particles and induces airway barrier injury by ROS. [4] This would result in the release of fibrotic inflammatory cytokines and trigger a wound-healing response that would eventually lead to pulmonary fibrosis. [4]

In an animal study, mice exposed to PHMG-P experienced difficulty breathing and exhibited pathological lesions similar to the pathological features observed in humans affected with IPF. [12] A time course of 10 weeks was even established for PHMG-P-induced pulmonary fibrosis. [12] Throughout this period, it was found that a single instillation of PHMG-P contributed to an increase in proinflammatory cytokine levels and elicited an influx of inflammatory cells into lung tissue. [12] This recruitment of inflammatory cells contributes to the deposition of ECM components in the lungs and, as a result, the development of IPF. The instillation of PHMG-P was also suspected of blocking T cell development and impairing its function in the immune system. [6] This would result in an insufficient resolution of inflammation caused by the increased levels of proinflammatory cytokines and result in stacked fibrotic changes and the progression of IPF. [6]

Another study claimed that PHMG-P could cause pulmonary fibrosis through the activation of the NF-κB signaling pathway. [9] Recall that the NF-κB signaling pathway is responsible for the production of proinflammatory cytokines associated with the development of IPF. According to the study, mice exposed to PHMG-P generated a large amount of ROS and produced significant levels of the cytokines IL-1β, IL-6, and IL-8 in a dose-dependent manner. [9] These cytokines produced by the NF- κB signaling pathway are known to activate the TGF-β signaling pathway, increase collagen production, and promote wound-healing and tissue remodeling responses. [4] As these responses are characteristic of IPF and the cytokines exhibited in this study are known to be produced through the activation of the NF-κB signaling pathway, there is strong evidence that PHMG-P can induce IPF through the NF-κB signaling pathway.

The Mechanism of IPF
TGF-β’s importance in the mechanism
Various studies of IPF have indicated that transforming growth factor β (TGF-β), one of the most significant fibrotic cytokines, plays a key role in the mechanism that induces IPF. TGF-β1 is credited with inducing the differentiation of fibroblasts to myofibroblasts and upregulating the secretion of ECM proteins (like collagen) in IPF. [13]

Specifically, growth factor TGF-β1 binds directly to the TGFβ receptor II (TGFβRII), triggering the recruitment and activation of receptor TGFβRI by TGFβRII. [14] This step leads to the increased production of collagen through the activation of a collection of proteins called the Smad 2/3 complex. [13] The activated Smad 2/3 complex accomplishes this by entering the nucleus to enhance the transcription of profibrotic genes such as those that produce collagen. [13] This idea has been heavily supported by experimental evidence. Exposure to the chemical DDAC was found to increase cellular mRNA levels of TGF-β1 by two-fold. [11] This increase contributed to the activation of the Smad 2/3 complex [11] and induced the differentiation of fibroblasts to myofibroblasts. [15] Overall, this led to the development of pulmonary fibrosis-causing fibrotic lesions in mice. [11]

In another study, TGF-β was found to promote the development of IPF by inhibiting the expression of the microRNA let-7d, driving epithelial-mesenchymal transition (EMT) and increased collagen deposition. [1] Typically, epithelial cells are important to maintaining lung functionality by acting as a barrier against pathogens and other harmful compounds and secreting protective substances. [4] During EMT, however, these cells increase in cellular motility [16] and are transformed into myofibroblasts, resulting in the acceleration of IPF. [4] Additionally, epithelial cells during EMT promote the recruitment of fibroblasts, while simultaneously inhibiting collagen degradation and elevating the levels of the tissue inhibitor of metalloproteinase 1 (TIMP-1). [4] TIMP-1 binds to metalloproteinase MMP2 to promote the growth of fibroblasts and myofibroblasts, accelerating ECM deposition while preventing its degradation. [12] This corroborates the claim that the TGF-β signaling pathway is a crucial component in the mechanism of IPF.

MicroRNA’s role in TGF-β regulation and pulmonary fibrosis
MicroRNAs are mRNA sequences that bind to complementary mRNA of proteins to prevent their translation and expression. They are also involved in multiple steps of fibrosis, such as cell proliferation, apoptosis, and differentiation. [16] During the progression of IPF, miRNAs are known to regulate the process in which epithelial cells transition into myofibroblasts (EMT) to promote fibrosis. [16] Since each miRNA is specific to a particular mRNA sequence, miRNAs may function as either promoters or inhibitors of IPF. One study found that the miRNA, miR-433, can act as a promoter of IPF by upregulating receptor TGFβRI and growth factor TGF-β1 to amplify TGF-β signaling. [13] In a separate study, it was confirmed that miR-30c-1-3p may act as a negative regulator of pulmonary fibrosis through targeting the mRNA and preventing the expression of receptor TGFβRII. [15]

In a study headed by the Department of Pathology at the University of Michigan Medical School, it was concluded that the development and pace of progression of IPF may be due to abnormal miRNA generation and processing. [1] It was found that in rapidly progressing IPF biopsies, five miRNAs significantly increased and one decreased when compared to slowly progressive biopsies. [1] This indicates that miRNAs have a significant influence on the mechanism of IPF. Additionally, members of the miR-30c and let-7d family significantly decreased in both forms of IPF when compared with unaffected individuals. [1] As stated previously, certain members of the miR-30c family are believed to be negative regulators of IPF and members of the let-7d family are inhibitors of EMT. All of the stated evidence signifies that miRNAs, in addition to the TGF-β signaling pathway, play important roles in the development of IPF.

Other factors to consider in the mechanism
The NALP3 inflammasome is another important factor to consider in the mechanism of IPF. The NALP3 inflammasome is an innate immune system receptor suspected of being the main cause of persistent inflammatory response and exacerbation of fibrotic changes. [12] According to a study focused on researching PHMG-P-induced fibrosis in mice, the activation of the NALP3 inflammasome appeared to contribute to fibroblast proliferation and the progression of IPF due to the production of the cytokine IL-1β. [12] IL-1β is known to increase the production of ROS needed to induce lung tissue damage by upregulating the expression of the cytokine chemokine (C-X-C motif) ligand 1 (CXCL1). [6] This upregulation of CXCL1 and resulting tissue damage was exhibited in the study, reinforcing the claim that the NALP3 inflammasome is a central component in the IPF mechanism. [12]

Secretory immunoglobulin A (sIgA), an antibody that has an important role in the immune system, also may have a role in the mechanism of pulmonary fibrosis. In a study supported by the Japan Society for the Promotion of Science, immunoglobulin A, the most abundant human immunoglobulin, was compared with TGF-β in its role in inducing pulmonary fibrosis and inflammation. [3] In this study, sIgA enhanced collagen production and induced responses in cytokines IL-6 and IL-8, and monocyte chemoattractant protein 1 (MCP-1). [3] MCP-1, similar to IL-6 and IL-8, is responsible for stimulating collagen synthesis and TGF-β production in fibroblasts. [6] It was concluded that under IPF, sIgA may make contact with lung fibroblasts and result in exacerbating airway inflammation and fibrosis through enhancing the production of inflammatory cytokines and ECM collagen. [3]

Potential therapeutic approaches and alternative methods of treatment
According to recent studies, only two drugs, pirfenidone and nintedanib, have been approved by the FDA for IPF treatment, and they have still failed to be significantly effective in treating the disease. [13] However, current studies on therapeutics that inhibit the TGF-β signaling pathway appear promising. Two particular drugs of interest are oridonin and matrine, along with their derivatives.

Oridonin, a major compound found in the herb Rabdosia rubescens, has been used in traditional Chinese medicine to treat inflammation and cancer for hundreds of years. [2] In a study focused on testing its effectiveness in treating IPF, it was found that exposure to oridonin significantly decreased the levels of three major biomarkers of fibrosis—hydroxyproline (HYP), beta silicomolibdic acid (β-SMA), and collagen, type 1, alpha 1 (COL1A1)—in a dose-dependent manner. [2] Additionally, oridonin attenuated pathological changes such as alveolar space collapse and infiltration of inflammatory cells. [2] Oridonin was able to achieve this through significantly inhibiting the upregulation of collagen production and the activation of Smad 2/3 in lung tissues, an important step in the progression of IPF through the TGF-β signaling pathway. [2] This presents a strong case for the use of oridonin as a treatment for IPF.

Matrine, similar to oridonin, also has roots in traditional Chinese medicine. Matrine has been shown in several studies to exhibit significant antifibrotic effects through the inhibition of the TGF-β pathway. In one study, matrine was shown to have an inhibitory effect against liver fibrosis by reducing the expression of TGF-β1 and instead increasing the expression of hepatocyte growth factor (HGF). [13] Through the inhibition of the TGF-β/Smad pathway, matrine was also shown to exhibit antifibrotic activities on cardiac fibrosis. [13] These antifibrotic effects are not just held by matrine, but their derivatives as well. The matrine derivative MASM was also shown to exhibit potent antifibrotic effects. [13] As the TGF-β signaling pathway is a central component in the mechanism of IPF, matrine and their derivatives present themselves as strong candidates for anti-IPF therapeutics.

Other drug candidates for the treatment of IPF are sesquiterpene lactones. Sesquiterpene lactones are naturally occurring compounds that are known to harbor extensive connections with the TGF-β1 signaling pathway. [5] This makes these compounds and their analogues strong drug candidates for IPF treatment. In one study, two out of 44 semi-synthetic analogues of sesquiterpene lactones were found to highly inhibit the TGF-β1 signaling pathway, ECM production, and the formation of fibroblasts. [5] This inhibition of ECM production and the formation of fibroblasts corroborates the claim that administering sesquiterpene lactones is an effective treatment for IPF.

As mentioned earlier, studies have shown microRNAs to be negative regulators of IPF. One study suggests that the replenishment of miR-30c may be a promising treatment. [15] Increased levels of miR-30c would promote the negative regulation of the TGF-β signaling pathway, suppressing the differentiation of myofibroblasts and preventing excessive collagen accumulation. In this manner, the replenishment of miR-30c would attenuate IPF symptoms. The inhibition of certain miRNAs, such as miR-34a, has also been shown to be an effective treatment. The inhibition of miR-34a by treatment with the caveolin-1 scaffolding domain peptide (CSP) was found to prevent pulmonary fibrosis by preventing the overgrowth of fibroblasts. [17] Although the manipulation of miRNA expression has been shown to have a large impact on the development of IPF, there is one issue with this method of treatment. A single miRNA can target thousands of mRNAs, making the function miRNAs have in pathophysiological events involved in IPF unclear. [17]

Conclusion
Although there is limited research on the etiology of IPF, this should only serve to motivate researchers to study its causes, mechanism, and potential treatments further. Thus far, the chemicals that have been shown to be potential inducers of IPF are PHMG-P, DDAC, PHMB, PGH, and the mixture of CMIT and MIT. However, out of all the chemicals, only PHMG-P has been heavily researched, and so additional studies are needed to confirm the other chemicals’ involvement in inducing IPF. Additionally, this research could be expanded upon through the study of the effects of other household disinfectants on the human body to determine whether they are also factors in inducing IPF. Besides the discovery of potential causatives, studies have also further illuminated details about the mechanism. Specifically attracting interest is the TGF-β signaling pathway in addition to miRNAs and their involvement in the regulation of IPF. Furthermore, the manipulation of TGF-β and miRNA levels with oridonin, matirne, and sesquiterpene lactones has been linked to favorable outcomes in the treatment of IPF. With further research, these treatments could become common practice and improve the quality of life for patients suffering from IPF.

 

References

  1. S. R. Oak et al., “A Micro RNA Processing Defect in Rapidly Progressing Idiopathic Pulmonary Fibrosis,” PLoS One, vol. 6, no. 6, p. e21253, Jun. 2011.
  2. Fu, Y., Zhao, P., Xie, Z., Wang, L., Chen, S., “Oridonin Inhibits Myofibroblast Differentiation and Bleomycin-induced Pulmonary Fibrosis by Regulating Transforming Growth Factor β (TGFβ)/Smad Pathway,” Med Sci Monit., vol. 24, pp. 7548–7555, 2018.
  3. Arakawa S., Suzukawa M., Watanabe K, Kobayashi K., Matsui H., Nagase T., Ohta K., “Secretory immunoglobulin A induces human lung fibroblasts to produce inflammatory cytokines and undergo activation,” Clinical and Experimental Immunology, vol. 195, no. 3, pp. 287–301, 2019.
  4. Kim, H.R., Lee, K., Park, C.W., Song, J.A., Shin, D.Y., Park, Y.J., Chung, K.H., “Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses,” Archive of Toxicology, vol. 90, pp. 617–632, 2016.
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  6. Song, J.A., Park, H., Yang, M., Jung, K.J., Yang, H., Song, C., Lee, K., “Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy,” Food and Chemical Toxicology, vol. 69, pp. 267–275, 2014.
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  8. Jung, H., Zerin, T., Podder, B., Song, H., Kim, Y., “Cytotoxicity and gene expression profiling of polyhexamethylene guanidine hydrochloride in human alveolar A549 cells,” Toxicology in Vitro, vol. 28, pp. 684–692, 2014.
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  10. Kim, H.R., Shin, D.Y., Chung, K.H.., “In vitro inflammatory effects of polyhexamethylene biguanide through NF-κB activation in A549 cells,” Toxicology in Vitro, vol. 38, pp. 1–7, 2017.
  11. Ohnuma-Koyama, A., Yoshida, T., Tajima-Horiuchi, H., Takahashi, N., Yamaguchi, S., Ohtsuka, R., Takeuchi-Kashimoto, Y., Kuwahara, M., Takeda, M., Nakashima, N., Harada, T., “Didecyldimethylammonium chloride induces pulmonary fibrosis in association with TGF-β signaling in mice,” Experimental and Toxicologic Pathology, vol. 65, pp. 1003–1009, 2013.
  12. Song, J., Kim, W., Kim, Y., Kim, B., Lee, K., “Time course of polyhexamethyleneguanidine phosphate induced lung inflammation and fibrosis in mice,” Toxicology and Applied Pharmacology, vol. 345, pp. 94–102, 2018.
  13. Li, L., Ma, L., Wang, D., Jia, H., Yu, M., Gu, Y., Shang, H., Zou, Z., “Design and Synthesis of Matrine Derivatives as Novel Anti-Pulmonary Fibrotic Agents via Repression of the TGFβ/Smad Pathway,” Molecules, vol. 24, no. 6, p. 1108, 2019.
  14. S. Ghatak et al., “Transforming growth factor β1 (TGFβ1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis,” J. Biol. Chem., vol. 292, no. 25, pp. 10490–10519, 23 2017.
  15. Wu, M., Liang, G., Duan, H., Yang, X., Qin, G., Sang, N.., “Synergistic effects of sulfur dioxide and polycyclic aromatic hydrocarbons on pulmonary pro-fibrosis via mir-30c-1-3p/ transforming growth factor β type II receptor axis,” Chemosphere, vol. 219, pp. 268–276, 2019.
  16. Shin, D.Y., Jeong, M.H., Bang, I.J., Kim, H.R., Chung, K.H.., “MicroRNA regulatory networks reflective of polyhexamethylene guanidine phosphate-induced fibrosis in A549 human alveolar adenocarcinoma cells,” Toxicology Letters, vol. 287, pp. 49–58, 2018.
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A Chemical Report on Heptachlor (Heptachlor Epoxide)

By Kaiming Tan

Author’s Note: This report analyzes and explains the biological, chemical, and environmental importance of heptachlor. More and more in today’s society, we are utilizing synthetic compounds as agricultural insecticides, which makes understanding what these chemicals do to our bodies and the environment of utmost importance. Farming strategies may seem far-removed from our daily lives, but these chemicals do not stay on the farm. They travel to our cities, to our grocery stores and markets, then make their way onto our dinner plates and into our children’s stomachs. I am constantly amazed at the power of scientific research to transform and demystify the detrimental nature of environmental and biological toxicants; this, combined with my passion in toxicology, has inspired me to research this topic and write this manuscript.

 

Keywords

Heptachlor, heptachlor epoxide, insecticide, environmental toxicology, biological toxin

 

Introduction

Heptachlor was introduced into the United States in the 1940s and 1950s, among the other chlorinated hydrocarbon insecticides, such as DDT (4). In 1971, 500,000 kilograms of heptachlor were applied to agricultural fields in soils and seeds to prevent termite infection in woods (4). However, after it became evident that heptachlor’s toxicity was a serious health concern, the Environmental Protection Agency (EPA) banned all registered use of heptachlor because of its carcinogenic properties and bioaccumulation in food and water. With the exception of treatment of fire ants in underground power transformers, there is no use of heptachlor in the United States now (2). In contrast, heptachlor is still used as an insecticide in some areas in Asia, Africa, and Eastern Europe (5). The form of greater toxicological concern is heptachlor epoxide, which is a metabolite of heptachlor in soil and the human body. Heptachlor epoxide is more toxic because it degrades slower than heptachlor, thus, is more persistent in the environment. Both heptachlor and heptachlor epoxide can be found in freshwater, estuarine, and marine systems (6). This review will cover the current literature on heptachlor toxicity and investigate the impact of heptachlor on biological systems.

 

Biological Fate (Absorption, Distribution, Metabolism, Elimination) 

Humans and animals can be exposed to heptachlor and heptachlor epoxide through soil, air and water; however, the main route of exposure is oral, through consuming contaminated food or drinking contaminated water. Children and infants are especially vulnerable to heptachlor exposure if they consume large amounts of breast milk from their mother. For instance, if the mother’s breast milk is contaminated by heptachlor, heptachlor can be easily consumed by the infant through breast milk feeding. In human breast milk, heptachlor epoxide was detected ranging from 0.13 to 128 ppb (parts per billion) (8). Another route of exposure is through inhalation. When heptachlor is deposited into the soil, it becomes heptachlor epoxide, which then spreads into the air. As a result, workers who use heptachlor to kill termites are potentially susceptible to inhaling heptachlor epoxide from the air (2). In addition, touching contaminated soils causes exposure to heptachlor dermally (1). 

Heptachlor persists in the environment after agricultural application. Even though there was no information on the background levels of heptachlor and heptachlor epoxide in the air or soil, there are 20 to 800 ppt (parts per trillion) heptachlor in drinking water and groundwater in the United States (2). Contaminated fish and shellfish were detected with levels of 2 to 750 ppb of heptachlor and 0.1 to 480 ppb of heptachlor epoxide. To date, there is no available data regarding the biological fate of heptachlor on humans. However, in rats, at least 50% of the orally-administered dose of heptachlor is absorbed in the gastrointestinal tract.The absorption is indicated by the presence of heptachlor and/or heptachlor epoxide in the rats’ liver (9). When heptachlor epoxide enters the bloodstream after absorption, it becomes the predominant metabolite in the body of laboratory female rats. Heptachlor epoxide in the bloodstream is positively correlated to the heptachlor dose administered (10). In other words, the higher heptachlor dose one consumed, the more heptachlor epoxide would appear in the bloodstream. 

Because of heptachlor epoxide’s high lipophilicity (likelihood in dissolving fats), its residue is found highest in adipose tissue in human infants (0.32±0.10ppm), while undetectable in the brain. These data also suggest that heptachlor epoxide can be transferred between pregnant women and their babies through the placenta (11). Furthermore, heptachlor and heptachlor epoxide can be stored in human breast milk. Jonsson et al.’s study in 1977 sampled the breast milk of 51 women who had no previously known exposure to heptachlor and detected an average concentration of heptachlor epoxide between 0.0027ppm and 0.019ppm (12). To the researchers, the results proved worrisome as the women’s breast milk contained high levels of heptachlor, which could damage the infant. The results were even more of a concern because there was no known interaction between the women studied and heptachlor.

After heptachlor is absorbed in the body, the primary metabolite of heptachlor in humans and rats is heptachlor epoxide. Heptachlor and heptachlor epoxide are usually metabolized by Cytochrome P450 (CYP450) enzymes. CYP450 enzymes are the body’s major class of enzymes responsible for detoxification. Moreover, heptachlor alters liver function by increasing gluconeogenic enzymes’ activities, which upregulates glucose synthesis from glycogen. Since most of heptachlor is metabolized in the liver, humans with liver diseases may have increased bioaccumulation of heptachlor epoxide because of decreased CYP450 enzyme activity (13). Despite the metabolism of heptachlor in the liver, most heptachlor epoxide can be stored in the adipose tissue because of its high lipophilicity and long half-life (1). 

In terms of excretion, orally-administered heptachlor in rats was excreted in the form of heptachlor epoxide and also as heptachlor. Radiolabeled heptachlor epoxide is excreted ten times more in the feces compared to urine after ten days of oral administration in rats, due to the high lipophilicity of heptachlor metabolites (8).

 

Mechanism of Action

The primary organ and organ systems that heptachlor targets are the liver, central nervous system and reproductive system, while secondary target organs include kidneys and lungs. Heptachlor is primarily metabolized in the liver into heptachlor epoxide, which has the same toxic potential. The reproductive system is a sensitive target for heptachlor toxicity because this system lacks a comprehensive detoxification system like the CYP450 enzymes in liver. CYP450 enzymes facilitate chemical reactions that chemically convert the toxicant into a more hydrophilic metabolite, thereby enhancing toxicant elimination by urine. Oral exposure of 1.8 mg/kg/day to female rats over 14 days caused decreased fertility due to decreased estradiol and progesterone levels. Estradiol and progesterone are important hormones produced by the ovaries, placenta, and adrenal glands; decreased levels may result in endocrine disruption and delayed sexual development. Oral exposure of 0.65 mg/kg/day over 70 days caused decreased sperm count in male rats. The mechanism of heptachlor’s reproductive toxicity remains unknown (1-2).

GABA, the molecule that normally binds the GABA receptor, is an amino acid which can also serve as an inhibitory neurotransmitter in the mammalian brain. Heptachlor primarily acts as a noncompetitive antagonist of the chloride channels of the GABAA receptors in mammals.  In other words, heptachlor blocks the Chlorine channel in the cells thus preventing GABAA activation (1-2, 14). By inhibiting the inhibitory neuron, heptachlor causes hyperexcitability of the cells. Although the heptachlor toxicity mechanism in liver is unknown, it is observed that in rats that presence of heptachlor elevates intracellular calcium levels and induces protein kinase C (PKC), which in turn activates the activator protein-1 DNA binding thereby causing tumorigenesis (2, 14). 

When animals are exposed to heptachlor above the toxic threshold, symptoms occur including tremors, convulsions, ataxia, and changes in EEG patterns (1). Also, rats who were orally exposed to >320 ppm of heptachlor had consistently lower body weight than rats that were unexposed (15). In humans, clinical symptoms of heptachlor toxicity include seizure, vomiting, and convulsions (2). 

Although heptachlor epoxide is theoretically an effective mutagen because of its high reactivity as an electrophile, research studies on heptachlor mutagenicity yielded mostly negative results. For example, heptachlor was not mutagenic in the auxotrophic strains of E. coli by reversion bioassays (14,15). In addition, heptachlor is proven to increase liver tumor incidence as an epigenetic promoter in previously initiated B6C3F1 mice. Heptachlor is a carcinogen in mice by inhibiting intercellular communications to promote tumor growth (14,16). On the other hand, research studies that investigate heptachlor’s teratogenicity, or tendency to disturb embryonic development, yielded mostly negative results. For instance, although feeding rats with diets containing heptachlor produces pups with higher mortality, no congenital malformation was found (2, 14, 17). 

In male rats, oral LD50 (lethal dose for 50% of the study population) of heptachlor is 40 to 100 mg/kg body weight based on data from two studies. In contrast, the oral LD50 of heptachlor in male chickens is 62 mg/kg body weight (1, 17). Symptoms displayed by heptachlor acute toxicity in animal subjects include hyperexcitability, tremors, convulsions and paralysis (18). 

Long-term exposure to heptachlor can cause liver damage in animals. In rats, prolonged exposure of sub-lethal doses of heptachlor is associated with increased CYP450 enzyme induction and other hepatic microsomal enzymes, in addition to liver hypertrophy (18). In humans, chronic exposure to heptachlor results in storage in adipose tissue and breast milk, because heptachlor is very lipophilic. Infants are at risk of being exposed to large doses of heptachlor if they consume contaminated breast milk (17). Despite the lack of human studies on long-term exposure, a multi-generation study conducted on rats concluded that oral exposure of 6 mg/kg/day of heptachlor is associated with decreased litter size, increased mortality and lens cataract (2). Because of its high lipophilicity, heptachlor residues can remain in the body over time. Heptachlor’s long-term toxicity damages the body gradually, further underlying the need for strict regulations of heptachlor use worldwide.  

 

Overview of Latest Research

Recent research on heptachlor focuses on its toxicity, specifically on the oxidative stress caused by heptachlor and its metabolism in aquatic animals. For example, Vineela et al.’s study investigates the impact of sub-lethal concentrations of heptachlor on carp fish Catla catla by measuring enzymatic activities of mostly Phase II enzymes (19). Phase II enzymes, a part of the CYP450 enzyme class, primarily perform conjugation reactions to convert the chemical into more water-soluble form to enhance urine elimination. Oral exposure of heptachlor at 1.46mg/L (20% of LC50 concentration) for 45 days causes a significant increase in lipid peroxidation, superoxide dismutase, glutathione-S-transferase and catalase activity in Catla catla. The results suggest that carp fish have a sensitive biological defense system against heptachlor, because low concentration activates the detoxification by increased biomarkers of primarily Phase II activity to prevent heptachlor toxicity and organ damage (19). 

In addition to heptachlor toxicity, current research also focuses on how to remove existing heptachlor from the environment via microbial degradation, as this method is more environmentally mindful and cost-effective than current physicochemical methods. Qiu et al.’s study discovered a novel strain of bacteria, named strain H, that can metabolize heptachlor efficiently. Strain H is a Gram-negative, short rod-shaped, single-cell bacterial strain that can degrade heptachlor at a rate of 88.2% degradation in 130 hours when exposed to 300 μg/L of heptachlor at 30oC. The main metabolites of heptachlor by strain H include heptachlor epoxide, chlordane epoxide, and 1-hydroxychorodene. This innovation allows possible bioremediation by microorganisms like strain H in heptachlor-contaminated soil and water to reduce heptachlor toxicity and threat to the environment and animals (20). 

Recent studies on heptachlor took a creative approach in gaining a deeper understanding in reducing heptachlor toxicity by enzymatic activity in aquatic model organisms and inventing novel microorganisms to metabolize heptachlor into less toxic metabolites. These new techniques will benefit public health by developing cost-effective ways for toxicant removal and controlling the environmental/biological fate of toxicants without causing additional harm.   

 

Conclusions

When initially used as an insecticide, heptachlor’s toxicity became a threatening health concern. The ban of commercial heptachlor use in the United States was a step in the right direction, as misuse of heptachlor can cause severe environmental consequences such as prolonged residue in soil and water habitats along with toxicities in humans and animals. Based on this research, other countries should pursue a substitute pesticide that has less potential for environmental and biological damage than heptachlor. 

Most studies conducted regarding heptachlor toxicity were conducted between the 1950s and the late 1980s. Future research can focus on the dose-response relationship of heptachlor exposure within large populations and whether genetic polymorphism contributes to the metabolism of heptachlor. Environmental toxicologists can also study the synergistic toxicity of heptachlor on environmental damage with other pesticides, since common pesticides often contain more than one chemical (1,2).

 

Acknowledgment

The author would like to thank Dr. Matthew Wood and Mr. Thomas Sears for providing feedback on early versions of this manuscript. 

 

Works Cited (in order of appearance) 

  1. Reed, N.R., & Koshlukova, S. (2014). Heptachlor. In Encyclopedia of Toxicology (pp. 840-844).
  2. United States. Agency for Toxic Substances Disease Registry, & Syracuse Research Corporation. (2007). Toxicological Profile for Heptachlor and Heptachlor Epoxide.
  3. Ivie, G., Knox, W., Khalifa, J., Yamamoto, R., & Casida, S. (1972). Novel photoproducts of heptachlor epoxide, Trans -chlordane, and Trans -nonachlor. Bulletin of Environmental Contamination and Toxicology, 7(6), 376-382.
  4. Hodgson, E. (2004). A textbook of modern toxicology (3rd ed.). Hoboken, N.J.: Wiley-Interscience.
  5. United States. Environmental Protection Agency. Office of Research Development. (2002). The Foundation for Global Action on Persistent Organic Pollutants a United States Perspective.
  6. Schimmel, S., Patrick, J., & Forester, J. (1976). Heptachlor: Toxicity to and uptake by several estuarine organisms. Journal of Toxicology and Environmental Health, 1(6), 955-965.
  7. Mnif, W., Hassine, A. I. H., Bouaziz, A., Bartegi, A., Thomas, O., & Roig, B. (2011). Effect of Endocrine Disruptor Pesticides: A Review. International Journal of Environmental Research and Public Health8(6), 2265–2303. http://doi.org/10.3390/ijerph8062265
  8. Savage, E., Keefe, T., Tessari, J., Wheeler, H., Applehans, F., Goes, E., & Ford, S. (1981). National study of chlorinated hydrocarbon insecticide residues in human milk, USA. I. Geographic distribution of dieldrin, heptachlor, heptachlor epoxide, chlordane, oxychlordane, and mirex. American Journal of Epidemiology, 113(4), 413-22.
  9. Tashiro, S., & Matsumura, F. (1978). Metabolism of trans -nonachlor and related chlordane components in rat and man. Archives of Environmental Contamination and Toxicology, 7(1), 113-127.
  10. Radomski, J., & Davidow, B. (1953). The metabolite of heptachlor, its estimation storage, and toxicity. The Journal of Pharmacology and Experimental Therapeutics, 107(3), 266-72.
  11. Curley, A., Copeland, M., & Kimbrough, R. (1969). Chlorinated Hydrocarbon Insecticides in Organs of Stillborn and Blood of Newborn Babies. Archives of Environmental Health: An International Journal, 19(5), 628-632.
  12. Adeshina, F., & Todd, E. (1990). Organochlorine compounds in human adipose tissue from north Texas. Journal of Toxicology and Environmental Health, 29(2), 147-156.
  13. Komori, Nishio, Kitada, Shiramatsu, Muroya, Soma, . . . Kamataki. (1990). Fetus-specific expression of a form of cytochrome P-450 in human livers. Biochemistry, 29(18), 4430-3.
  14. Whitacre, David M. (2008). Reviews of Environmental Contamination and Toxicology(Vol. 234). New York, NY: Springer New York.
  15. Moriya, Ohta, Watanabe, Miyazawa, Kato, & Shirasu. (1983). Further mutagenicity studies on pesticides in bacterial reversion assay systems. Mutation Research, 116(3-4), 185-216.
  16. Williams, G., & Numoto, S. (1984). Promotion of mouse liver neoplasms by the organochlorine pesticides chlordane and heptachlor in comparison to dichlorodiphenyltrichloroethane. Carcinogenesis, 5(12), 1689-96.
  17. United Nations Environment Programme, World Health Organization, International Labour Organisation, & Commission of the European Communities. (1976). Environmental health criteria. Geneva: World Health Organization.
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  20. Qiu, Liping, Wang, Hu, & Wang, Xuntao. (2018). Conversion mechanism of heptachlor by a novel bacterial strain. RSC Advances, 8(11), 5828-5839.

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