Biochemical and Molecular Bases of Lead-Induced Toxicity in

Sep 4, 2018 - Biography. Prof. (Dr.) Bechan Sharma of the University of Allahabad obtained his higher education from BHU-Varanasi and CDRI-Lucknow, ...
0 downloads 0 Views 1MB Size
Subscriber access provided by UNIV OF DURHAM

Review

Biochemical and Molecular Bases of Lead induced toxicity in mammalian systems and possible mitigations Nitika Singh, Abhishek Kumar, Vivek kumar Gupta, and Bechan Sharma Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.8b00193 • Publication Date (Web): 04 Sep 2018 Downloaded from http://pubs.acs.org on September 5, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Chemical Research in Toxicology

1

Biochemical and Molecular Bases of Lead induced toxicity in mammalian systems and

2

possible mitigations

3

Nitika Singh, Abhishek Kumar, Vivek Kumar Gupta and Bechan Sharma*

4

Department of Biochemistry, Faculty of Science, University of Allahabad, Allahabad-211002,

5

India

6

*

corresponding author: Email: [email protected]; Contact: +91-9415715639

7 8

Table of Contents (TOC) graphic

9 10 11 12 13 14 15 16

Abstract

ACS Paragon Plus Environment

Chemical Research in Toxicology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 35

17

The effects of lead exposure on to the mammals are reported to be devastating. Lead is present in

18

all the abiotic environmental components such as brass, dust, plumbing fixtures, soil, water, and

19

lead mixed imported products. Its continuous use for several industrial and domestic purposes

20

has caused rise in its levels thereby posing serious threats to human health. The mechanisms

21

involved in lead-induced toxicity primarily include free radical mediated generation of oxidative

22

stress which directly imbalance the prooxidants and the antioxidants in body. The toxicity of lead

23

involves damage primarily to major biomolecules (lipid, protein and nucleic acids) and liver

24

(hepatotoxicity),

25

(genotoxicity), present in animals and humans. The activation of c-Jun NH2-terminal kinase

26

(JNK), Phosphoinositide (PI) 3-kinase or Akt and p38 mitogen activated protein kinase (MAPK)

27

signaling pathways are important for lead cytotoxicity. Lead increased apoptosis through

28

signaling cascade and associated factors and significantly impairs cell differentiation and

29

maturation. In addition, lead has the great impact on metabolic pathways such as heme synthesis

30

thereby leading the onset of anemia in lead exposed people. This review encompasses an updated

31

account of varied aspects of lead induced oxidative stress and their biomolecular consequences

32

such as perturbations in physiological processes, apoptosis, carcinogenesis, hormonal imbalance

33

and loss of vision and reduced fertility and their possible remediation through synthetic

34

(chelators) and natural compounds (plant-based principles). This communication primarily

35

concerns with the biomedical implications of lead induced generation of free radical and their

36

toxicity management in mammalian system.

nervous

system

(neurotoxicity),

kidney

(nephrotoxicity)

and

DNA

37 38

Keywords: Lead, Oxidative stress, Toxicity, Signaling pathways, Apoptosis, Carcinogenesis and

39

Remediation

40 41

1. INTRODUCTION

42

Lead is the one of the crucial and natural toxic metal among all the heavy metals1 of the earth’s

43

crust. Lead originated from Latin word plumbum, atomic number 82, is a widely distributed

44

toxin. The use of lead can be retraced from the ancient times2. Lead is detectable in all phases in

45

living systems as well as inert environment. The enhanced anthropogenic activities and vehicular

46

emissions are mainly responsible for increase in the lead level in human body through inhalation,

47

ingestion and dermal contact. Lead in the form of a toxin induces various biochemical,

ACS Paragon Plus Environment

Page 3 of 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Chemical Research in Toxicology

48

physiological and behavioral dysfunctions. Particularly liver, spleen, and kidney have been

49

reported as key target sites for lead toxicity3. Virtually in all heavy metals lead is toxic

50

abundantly to humans from thousands of years. On entering in our bodies with food, air and

51

water lead induces toxicity by interacting with cellular compounds which contain sulfur, oxygen,

52

or nitrogen elements2. Increased blood lead levels are primary diagnosis of lead toxicity.

53

However, acute exposure to lead results in several malfunctioning such as neurobehavioral and

54

neurological damage, cognitive dysfunction, hypertension, as well as renal impairment. Among

55

the parts of the human body and systems hematopoietic, renal, reproductive, and central nervous

56

system are more vulnerable toward the dangers from exposure to high level of lead4. According

57

to Jalali et al. (2017), the elevation of malondialdehyde (MDA) level increases erythrocyte

58

superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities along with rise in total

59

leukocyte, lymphocyte and neutrophil counts resulting into microcytic anemia in the lead treated

60

rats5. Chelation therapy is the conventional suggestion for low level lead poisoning with brain

61

(encephalopathic) damage. However, the treatment with low-amount but for longer duration is

62

still under investigation. Issues surrounding the assessment of body lead burden and the

63

consequences of low-level environmental exposure are critical in the treatment of chronic

64

diseases. Although co-administration of antioxidants such as natural, herbal, synthetic or another

65

chelating agent have been reported to improve the effect of toxic metals5,6. It is required to

66

develop preexisting or newer chelating agents to reap real benefit with the least side effects

67

during combination therapy in association with those of antioxidants. In animal models, the

68

clinical recoveries are possible to be done by the same. The present review article summarizes

69

the recent account of lead toxicity in mammalian systems, targets, mechanisms of actions and

70

possible amelioration using the synthetic chelators and plant products.

71

2. SOURCES OF LEAD EXPOSURE

72

Among the heavy metals, lead is highly persistent in nature. The various sources of lead in the

73

environment include groundwater, soil, dust of metal ores, brass plumbing fixtures, several

74

industrial activities, folk remedies, combustion of petroleum, manufacturing of lead-battery,

75

paint industries, and mining processes contaminated food, and certain herbal products

76

manufactured in combination with lead1. (Figure 1). Humans are continually exposed to lead

77

from numerous sources such as contaminated air, water, soil, house dust and food via food chain

78

and inhalation. In children, lead paints and lead chips are primary and major sources of lead

ACS Paragon Plus Environment

Chemical Research in Toxicology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

79

intoxication. According to U.S. Department of Housing and Urban Development, about 38

80

million houses in United States use lead-based paints. The report suggests that around 24 million

81

of those houses comprise significant lead-based paint hazards, which also include deteriorating

82

paints and/or dust or soil contamination at outside the home7. Manufacturing process of lead-

83

based products may release as pollutants and mix with soil and water which enter in the body

84

through food, water and air8. Inadvertent ingestion is another way of exposure to lead-

85

contaminated soil, dust particles and lead-based paint. The growing population including

86

children, infants in neonatal periods, and the fetus are most susceptible to lead poisoning9. In

87

daycare centers and schools plumbing components containing lead contribute to significant

88

amount of lead in drinking water. Also, the ceramics and food containers painted with lead-based

89

paint / lead-containing glaze contribute to sufficient amount of lead (Figure 1). The lead

90

containing occupational areas have higher levels of lead, so workers from these areas have been

91

reported to get greater chances of lead-exposure. Some other sources of lead poisoning are

92

manufacture of ammunition, batteries, ceramic glazes, circuit boards, caulking, sheet lead,

93

solder, some brass and bronze plumbing, radiation shields, intravenous pumps, fetal monitors,

94

and some surgical equipment and military equipment such as jet turbine engines, military

95

tracking systems etc. (Figure.1). Workers have a greater risk to lead exposure at various

96

construction sites10,11.

97

ACS Paragon Plus Environment

Page 4 of 35

Page 5 of 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Chemical Research in Toxicology

98 99

Figure 1. Sources of lead in the environment.

100

3. LEAD IN CELLULAR AND REDOX ENVIRONMENT

101

The balance and stability between the generation of reactive nitrogen species (RNS), reactive

102

oxygen species (ROS) and elimination of these species by antioxidant molecule and antioxidant

103

defense system of the cell is known as the redox environment of the cells12 (Table 3). The

104

production and removal of ROS influence the cellular redox environment. An environmental

105

toxicant, lead involve in production of (ROS) during oxidative stress (OS)13. OS induced by lead

106

toxicity is associated with several pathophysiological condition including oxidative damage to

107

different body organs such as heart, kidneys, brain, and reproductive organs14. ROS are the

108

products of cellular metabolism. The concentration of ROS molecules depends on concentrations

109

and duration of xenobiotics exposure. ROS can be both beneficial and harmful to the tissues.

110

Normally, ROS molecule functions as messengers in various cellular signaling and regulation of

111

cellular processes, such as cell proliferation15 (Table 3).

112 113

ACS Paragon Plus Environment

Chemical Research in Toxicology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

114

4. MECHANISM OF ACTION

115

In 1965, the earlist paper related to lead mediated OS was published. In this investigation,

116

several metals were found to enhance the rate of essential fatty acids oxidation. That time lead

117

was reported to be ineffective. Many years later, it was observed that lead was reponsible for

118

increase in lipid peroxidation as analysed by malondialdehy (MDA). Further, several researchers

119

reported the lead induced lipid peroxidation in rat brain. A direct correlation has been recorded

120

by Shafiq-ur-Rehman (1984) between increase in the lead concentration and the increase in lipid

121

peroxidaton. Similarly, in the liver tissues similar effect was observed16. The mechanisms

122

involved in lead-mediated OS primarily involves (Figure 2) damage to membrane and DNA of

123

cell as well as damage to certain enzymes including catalase, GPx, SOD, and glucose-6-

124

phosphate dehydrogenase (G6PD) and non-enzymatic antioxidant molecules including thiols

125

(GSH) in mammalian systems17,18.

126

A number of investigations have indicated the involvement of multifactorial mechanism in

127

metal-induced toxicity (Figure 3). These multifactorial mechanisms can be associated to the OS,

128

enzyme inhibition, DNA damage, and change in gene expression and adventitious like mimicry.

129

Metal induced generation of free radical especially ROS are well known mechanism (Table 3)

130

(Figure 3). The mechanisms that enable lead for induction of OS are not clearly mentioned

131

because lead can not readily undergo valance change. The electron-sharing affinities of lead form

132

covalent bonding with sulphydryl groups. Lead and GSH interaction is essential for its toxic

133

response19. In case of signaling pathway, Lead mimics as calcium and binds with calmodulin

134

protein (Ca2+-binding protein) that has been identified to inducing lead toxicity. The relative

135

affinity of lead binding is higher than calcium20 (Figure 4). Different types of mechanisms have

136

been proposed for lead medieted OS: (a) Direct effect of lead on cell membranes, (b) Lead-

137

hemoglobin interactions, (c) δ-aminolevulinic acid (δ-ALA)–mediated generation of ROS, and

138

(d) Effect of lead on the antioxidant defense system of cells.

ACS Paragon Plus Environment

Page 6 of 35

Page 7 of 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Chemical Research in Toxicology

139 140

Figure 2. Overview of mechanism of action and molecular targets of lead. Lead exposure causes

141

oxidative stress by increasing the level of free radicals and decreasing the antioxidant defense

142

system inside the cell. Primarily, it involves damage to major biomolecules (such as lipid,

143

protein and nucleic acids) leading to the altered cellular functions causing necrosis or cell death.

144 145

5. BIOMOLECULAR PATHWAYS OF LEAD POISONING

146

Lead toxicity can affect every organ system. Lead induces a broad range of biochemical,

147

physiological, and genetic dysfunctions (Figure 3). It includes the ability of lead to inhibit /

148

mimic the actions of Ca++ (calcium-dependent or similar processes can be affected) and also

149

interact with some proteins (such as those with amine, carboxyl, phosphate and sulfhydryl,

150

groups). Lead induced bimolecular consequences in living cells given as below:

151 152

5.1. NEUROTOXICITY BY LEAD AND ITS ACTION

153

Nervous system is one of the most sensitive targets of lead exposure. Generally, it causes

154

neurotoxicity but decreases pediatric cognitive functions significantly. The excess generation of

ACS Paragon Plus Environment

Chemical Research in Toxicology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

155

free radicals are also associated with neurotoxicity by causing perturbations in the brain

156

functions. Since Lead efficiently crosses the blood brain barrier (BBB) and it easily substitutes

157

calcium ions and thus, interrupts its intracellular activities by interfering with the regulatory

158

actions of calcium in brain cells21. In children, long term exposure to lead may result in frequent

159

occurrence of coma, seizures, and altered mental status.

160

Several clinical studies are conducted on relationship of Lead poisoning and its effect on

161

neurological development and functions. The outcome of these clinical reports significantly

162

(P