Essential- (Cobalt, Chromium, Molybdenium and Nickel) And Non-Essential- (Aluminium, Beryllium and Boron) Heavy Metals in Patients with Breast- or Cervical- Cancer.
Jimoh Mutiu Alani1, Edem Fabian Victory2, Arinola Ganiyu Olatunbosun3
1.Department of Radiation Oncology, University of Ibadan and University College Hospital,
Ibadan, Nigeria. 2. Department of Immunology, University of Ibadan, Nigeria.
3. Faculty of Basic Medical Sciences, KolaDaisi University, Ibadan.
ABSTRACT
Background: There are 23 heavy metals with wide environmental distribution and they are known to induce multiple organ damage even at low levels of exposure. Despite the high degree of toxicity and public health significance of heavy metals, their toxicity depends on their dose, route, host age, gender or organ type. However, Nickel, Chromium, Cobalt, Beryllium, Molybdenum, Boron and Aluminium are less studied in cancers. Objectives: To determine the plasma concentrations of essential (cobalt, chromium, molybdenum and nickel) and non-essential (aluminium, beryllium and boron) heavy metals in Nigerian females with breast cancer or cervical cancer. Method: This study was undertaken to determine plasma cobalt, chromium, molybdenum, nickel, aluminium, beryllium, nickel and boron in 30 breast cancer patients and 30 cervical cancer patients attending University Teaching Hospital, Ibadan, Nigeria; and 30 healthy female control using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). Descriptive statistics was done, with statistical significance set at p≤ 0.05. Results: The mean plasma cobalt, chromium, molybdenum, nickel, aluminium, beryllium, nickel and boron were not significantly increased in cervical cancer patients or significantly decreased in breast cancer patients compared with healthy female control. However, the mean plasma cobalt, chromium, molybdenum, nickel, aluminium, beryllium and boron were significantly increased in cervical cancer patients compared with breast cancer patients. When stage 2 cervical cancer patients was compared with stage 2 of breast cancer, the mean plasma cobalt, chromium, molybdenum, nickel, aluminium, beryllium and boron were significantly increased in cervical cancer patients compared with stage 2 breast cancer patients. Conclusion: This study revealed that concentrations of heavy metals vary with cancer types. Therefore, differential nutritional supports and chelation therapy for the management of cancer patients will be needed for different cancers.
Keywords: Carcinogenicity, Female cancers, Heavy metals, Mechanistic action, Nutritional support.
Correspondence
Arinola Ganiyu Olatunbosun
Department of Immunology, University of Ibadan, Nigeria
and Faculty of Basic Medical Sciences, KolaDaisi University,
Ibadan.
+234-80-98121520
INTRODUCTION
Heavy metals are metallic elements with a relatively high density compared to water and induce toxicity at low level of exposure.1Increasing industrial, agricultural, domestic and technological applications have led to inevitable human exposure to these metals2 causing toxicity of varied gravities in different organs and gender.1 Generally, heavy metals can be classified into essential- and non-essential- heavy metals. Essential heavy metals play important roles in human biological functions such as metabolic function, oxidative stress regulation, and embryonic development. Non-essential heavy metals are harmful to health even at low concentrations and have no established biological functions.3The most widely studied heavy metals in relations to cancers are lead, mercury, arsenic, cadmium, antimony and radium4, 5 while cobalt, chromium, molybdenum, nickel, aluminium, beryllium and boron are relatively less studied. In this study, we determined the plasma concentrations of “neglected” heavy metals [essential (cobalt, chromium, molybdenum and nickel) and non-essential (aluminium, beryllium and boron)]in female patients having breast- or cervical- cancer, so as to increase our knowledge on better management, pathogenesis and prevention of cancers.
Generally, heavy metal induced toxicity and carcinogenicity through many mechanistic aspects, some of which are not clearly elucidated. Several studies have demonstrated that reactive oxygen species (ROS) and oxidative stress which induce multiple organ damage, even at lower levels of exposure play a key role in the toxicity of metals.1,6 Inflammation, microbiomes, oxidative stress, metals and micronutrients underlie cancer susceptibility and progression. Cancer patients are characterized by a variety of perturbations in homeostasis of metal ions such as zinc, iron, selenium and copper both at intratumoral or systemic level, and studies have shown that metal dysregulation triggers neoplastic transformation of cells.5-8 Also, epigenetic changes via chromatin immunoprecipitation sequencing, DNA methylation and bisulphite sequencing were implicated in cancers.8, 9
Apart from the fact that bio-accumulated toxic elements interact with DNA leading to cell cycle modulation, carcinogenesis or apoptosis, heavy metals also cause diversity of toxic effects on a variety of cellular organelles, enzymes, body tissues and organs to disrupt growth, proliferation, differentiation, damage-repairing processes, and apoptosis.10Therefore, suggesting the involvement of “neglected” heavy metals in carcinogenesis. The authors of the present study therefore aimed to assess the plasma concentrations of “neglected” heavy metals in two female gynaecological cancers, so as to improve their managements.
MATERIALS AND METHODS
Thirty (30) cervical cancer patients, 30 breast cancer patients and 30 age matched females without cancer as control subjects were recruited for this study. This was a case-control study where all patients were not on any treatment and were voluntarily recruited at random during visit to the clinic. Patient socio-demographic information is given in Table 1. Ethical approval for the study was obtained from joint University of Ibadan and University College Hospital, Ibadan, Nigeria Research Ethics Committee (UI/EC/23/0065). Plasma separated from five (5) ml of venous blood plasma was analysed for the concentrations of essential (cobalt, chromium, molybdenum and nickel) and non-essential (aluminium, beryllium and boron) heavy metals using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). The mean and standard deviations of the data were presented as Tables and the difference between mean (± standard deviation) of the heavy metals between two groups was determined using Student t-test. p ≤ 0.05 was taken as significant.
RESULTS
The mean plasma cobalt, chromium, molybdenum, nickel, aluminium, beryllium and boron were non-significantly increased in cervical cancer patients and non-significantly decreased in breast cancer patients compared with healthy female control. However, the mean plasma cobalt, chromium, molybdenum, nickel,
Table 1: Sociodemographic Characteristics of Breast Cancer Patients.
Table 2: Comparison Of Mean ± S.D Of Heavy Metals In Cervical Cancer With Breast Cancer Patients And Control.
*Significantly different between cervical cancer and breast cancer
Table 3: Comparison of Mean ± S.D of heavy metals in stage 2 cervical cancer with stage 2 breast cancer patients
*Significantly different from stage 2 of cervical cancer patients
aluminium, beryllium and boron were significantly increased in cervical cancer patients compared with breast cancer patients (Table 2). Because of the few numbers of stages 1 and 3 in breast- and cervical- cancer patients considered for this study, heavy metals in only stage 2 of breast cancer patients were compared with stage 2 of cervical cancer patients. The mean level of cobalt, chromium, molybdenum, nickel, aluminium, beryllium and boron were significantly increased in stage 2 cervical cancer patients compared with stage 2 breast cancer patients (Table 3).
Heavy metals exhibit an immense bio-accumulating range of toxic effects with regard to carcinogenesis.1-5Therefore, effective educational programs are needed to raise awareness of the risks associated with exposure to heavy metals. It is a known fact that the mechanism of heavy metal toxicity varies widely. Also, cobalt, chromium, molybdenum, nickel, aluminium, beryllium, nickel and boron are lessstudied in relation to cancers. Therefore, the reason for the execution of present study. Advances in boron anticancer effort includes a wide-scale application in Boron Neutron Capture Therapy (BNCT), a radiotherapy based of high boron uptake capacity by cancer cells.10-12The present study observed raised level of boron in cervical cancer patients. A previous study reported that boron activity during carcinogenesis are inhibition of a serine proteases and NAD-dehydrogenases activities, mRNA splicing, cell division, receptor binding mimicry, and the induction of apoptosis.13
Although aluminium has no known biological function, but wide exposure to aluminium14make its contribution to cancer a possibility. The fact that aluminiumlevel was increased in cervical cancer patients compared with breast cancer patients or healthy control is an indication thataluminium contributes to carcinogenesis varies with organs. Aluminium is excreted primarily through urine with a very small amount in faeces.15It is therefore likely thataluminium is excreted more by breast cancer patients than cervical cancer patients, thus recommending a search into the urine concentration of aluminium in these groups of patients. Aluminium is a toxic non-essential metal inhibiting hexokinase, phosphodiesterase, alkaline phosphatase and phosphoxidase due to its greater affinity to DNA and RNA.16Aluminium imbalance causes nausea, vomiting, diarrhea, loss of memory and loss of co-ordination.17, 18Since vomiting and diarrhoea results to electrolyte dysregulation, it is therefore likely that dys-electrolyteamia observed in cancer patients might have aluminium-based mechanism.
Chromium exposure damages respiratory, kidney, liver, circulatory and nerve tissues but the main health problems associated with chromiumtoxicity is with the reproductive system.19, 20Thus, supporting increased chromium level seen in cervical patients.21Chromium toxicity leads to chromosomal abnormalities, DNA strand breaks22and disruption of cellular integrity and functions23 but the gravity of this varies with chromium sub-types(Cr1-4).24 Future study into plasma concentrations of chromium sub-types (Cr1- Cr4) in cancer patients will be beneficial. Nickel promotes hypoxia inducing factor (HIF)-α and chromosomal aberrations.25, 26Global DNA hypo-methylation and gene-specific hyper-methylation are found in nickel carcinogenesis.27, 28 Epidemiological studies have revealed a significant correlation between nickel exposure and the incidence of carcinogenesis in breast and ovary29-32, therefore supporting the involvement of nickel level in breast- and cervical- cancers as shown by the results of present study.
Inhalation through occupational exposure is the main route of beryllium-human contact, but there is little conclusive evidence to suggest that exposure to either beryllium-salts or beryllium-metal particles lead to genotoxicity.33Beryllium bind MHC-peptide complex which recogniseCD4+ T-cell receptors to initiate hyperactive response34and autoimmune phonomenon.35This, therefore provide basis to investigate autoimmune and hypersensitivity in cancer patients. In experimental animals, beryllium causes adenocarcinomas, osteosarcomas and produced chromosomal breaks35and inhibition of DNA repair synthesis36, thus contributing to cervical cancer as shown in this study.
Different epidemiological studies provide relatively sparse and contradictory data on the carcinogenicity of cobalt to humans.37, 38 The result of this present study shows no significant differences in the levels of cobalt in cancer patients and unaffected control. Cobalt mimic estradiol by binding to and activating estrogen receptor-alpha.38Therefore, involvement of cobalt in female cancers may not be doubtful.
According to Huang et al39 molybdenum is an essential trace element mainly stored in the liver, kidneys, glands and bones. It is also present in the lungs, spleen, skin and muscles. Problems caused by the shortage of molybdenum include intellectual disability, seizures, severe hypertension, tachycardia, nausea, vomiting and coma. Too much molybdenum can cause symptoms similar to gout and other problems involving the gastrointestinal tract, liver and kidneys. Free molybdenum combines with the four sulphur atoms to form tetra-thiomolybdate, which in turn reduces circulating copper and copper dependent binding proteins. Thus, excess molybdenum as seen in cervical cancer patients is unhealthy.
CONCLUSION
Considering the varied concentrations of “neglected” heavy metals in different cancer types, nutritional supports and chelation therapy for the management of cancer patients may be individualised. Because of relatively small number of cancer cases, the results must be interpreted with caution. However, further search for agents to mitigate carcinogenic potential of heavy metals will be beneficial as a new protective target to cancers.
Strength of the study: The study is extensive since it involved 7 “neglected” heavy metals on two different female cancers.
Limitations of the Study: The study was limited because of its small sample size which inhibits comparison between different cancer stages.
Funding sources: Nil
Conflict of interest: Nil
REFERENCES