The Connection Between LPS, Mercury and Other Heavy Metals.
There is a synergetic connection between LPS and heavy metal poisoning.
LPS toxicity makes the mice studied more susceptible to mercury damage.
The reverse is also true: Mercury toxicity makes the mice more
susceptible to LPS damage. Other Heavy Metals act in a similar
fashion with LPS.
Even mice who have a genetic resistance to mercury-induced autoimmunity became susceptible to mercury-induced autoimmunity when they were exposed to LPS. The research indicates that activation of the innate immune system with LPS plays a key role in the induction as well as the severity of heavy metal induced autoimmunity. This information is very
relevant to the ASD community since the similarities between autism and
other autoimmune diseases suggest that autoimmunity may be a critical
factor in the cause of autism.
The fact that LPS injections have been found to cause a significant
glutathione (GSH) reduction in rats is another very important
connection. Decreased glutathione levels impair detoxification.
Acute LPS injection produced a significant Glutathione (GSH) reduction
View this article in PubMed
1: Neurochem Int. 2007 Mar;50(4):671-80. Epub 2007 Jan 13.
Altered glutathione homeostasis in animals prenatally exposed to lipopolysaccharide.
* Zhu Y,
* Carvey PM,
* Ling Z.
Department of Pharmacology, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA; Fujian Institute of Geriatrics, Union Hospital, Fujian Medical University, Fuzhou, Fujian 350001, China.
We previously reported that injection of bacterial lipopolysaccharide (LPS) into gravid female rats at embryonic day 10.5 resulted in a birth of offspring with fewer than normal dopamine (DA) neurons along with innate immunity dysfunction and many characteristics seen in Parkinson's disease (PD) patients. The LPS-exposed animals were also more susceptible to secondary toxin exposure as indicated by an accelerated DA neuron loss. Glutathione (GSH) is an important antioxidant in the brain. A disturbance in glutathione homeostasis has been proposed for the pathogenesis of PD. In this study, animals prenatally exposed to LPS were studied along with an acute intranigral LPS injection model for the status of glutathione homeostasis, lipid peroxidation, and related enzyme activities. Both prenatal LPS exposure and acute LPS injection produced a significant GSH reduction and increase in oxidized GSH (GSSG) and lipid peroxide (LPO) production. Activity of gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in de novo GSH synthesis, was up-regulated in acute supranigral LPS model but was reduced in the prenatal LPS model. The GCS light subunit protein expression was also down-regulated in prenatal LPS model. GSH redox recycling enzyme activities (glutathione peroxidase, GPx and glutathione reducdase, GR) and glutathione-S-transferase (GST), gamma-glutamyl transpeptidase (gamma-GT) activities were all increased in prenatal LPS model. Prenatal LPS exposure and aging synergized in GSH level and GSH-related enzyme activities except for those (GR, GST, and gamma-GT) with significant regional variations. Additionally, prenatal LPS exposure produced a reduction of DA neuron count in the substantia nigra (SN). These results suggest that prenatal LPS exposure may cause glutathione homeostasis disturbance in offspring brain and render DA neurons susceptible to the secondary neurotoxin insult.
PMID: 17291629 [PubMed - in process]
View this article in PubMed
1: Toxicology. 2000 Aug 21;149(2-3):75-87.
Potentiation of mercury-induced nephrotoxicity by endotoxin in the Sprague-Dawley rat.
Department of Veterinary Pathology, G303 Veterinary Medical Center, Michigan State University, East Lansing, MI 48824-1314, USA. firstname.lastname@example.org
Endotoxin (lipopolysaccharide; LPS) and mercury are nephrotoxic compounds of food safety concern. Endotoxin is a product of cell walls of gram negative bacteria. Humans are constantly exposed to LPS through food, water and air. Food is the main source of mercury exposure for humans. Endotoxin potentiates the toxicity of a number of xenobiotics, but its interaction with nephrotoxic heavy metals has not been investigated. We tested the hypothesis that endotoxin enhances mercury-induced nephrotoxicity. Thirty-two, 41-43-day-old, male Sprague-Dawley rats were allocated randomly to four groups of eight rats each as follows: group I received 0.9% sodium chloride, group II received 2.0 mg of Escherichia coli 0128:B12 LPS kg(-1) once, group III received 0.5 mg mercuric chloride kg(-1) once, and group IV received 2.0 mg E. Coli 0128:B12 LPS kg(-1) once 4 h before receiving 0.5 mg mercury chloride kg(-1) once. Mercury, LPS and 0.9% sodium chloride were all injected IV through the tail vein. Rats were monitored for 48 h after mercury injection. Serum creatinine, urea nitrogen, and polyuria were significantly increased in rats given LPS plus mercury relative to those given either agent alone or saline (P=0.05). The most severe morphologic lesions were found in rats given LPS plus mercury, which also had significantly greater renal mercury concentration than those given mercury alone (P < or = 0. 05). In conclusion, LPS potentiated mercury-induced nephrotoxicity.
PMID: 10967405 [PubMed - indexed for MEDLINE]
View this article in PubMed
1: Clin Exp Immunol. 2005 Aug;141(2):238-47. Links
Bacterial lipopolysaccharide both renders resistant mice susceptible to mercury-induced autoimmunity and exacerbates such autoimmunity in susceptible mice.
Department of Biochemistry and Biophysics, Arrhenius Laboratories for the Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden. email@example.com
The initiation and severity of systemic autoimmune diseases are influenced by a variety of genetic and environmental factors, in particular bacterial infections and products. Here, we have employed bacterial lipopolysaccharide (LPS), which non-specifically activates the immune system, to explore the involvement of innate immunity in mercury-induced autoimmunity in mice. Following treatment of mouse strains resistant [DBA/2 (H-2(d))] or susceptible [SJL(H-2(s))] to such autoimmunity with mercuric chloride and/or LPS or with physiological saline alone (control), their immune/autoimmune responses were monitored. Resistant DBA/2 mice were rendered susceptible to mercury-induced autoimmunity by co-administration of LPS, exhibiting pronounced increases in the synthesis of IgG1 and IgE, high titres of IgG1 deposits in the kidneys and elevated circulating levels of IgG1 antibodies of different specificities. Furthermore, the percentages of the T cells isolated from the spleens of DBA/2 mice exposed to both mercury and LPS that produced pro-inflammatory cytokines were markedly increased by in vitro stimulation with phorbol myristate acetate (PMA) and ionomycin, which was not the case for splenic T cells isolated from mice receiving mercuric chloride, LPS or saline alone. In addition, exposure of susceptible SJL mice to mercury in combination with LPS aggravated the characteristic features of mercury-induced autoimmunity, including increased synthesis of IgG1 and IgE, the production of IgG1 anti-nucleolar antibodies (ANolA) and the formation of renal deposits of IgG1. In summary, our findings indicate that activation of the innate immune system plays a key role in both the induction and severity of chemically induced autoimmunity.
PMID: 15996188 [PubMed - indexed for MEDLINE]
Other Heavy Metals interact in similar fashion with LPS. Here is one
example among various articles about synergistic interaction between
other heavy metals and LPS. (This one comes from PubMed.)
View this article in PubMed
Evidence for a synergistic interaction between cadmium and endotoxin toxicity and for nitric oxide and cadmium displacement of metals in the kidney.
* Satarug S,
* Baker JR,
* Reilly PE,
* Esumi H,
* Moore MR.
National Research Centre for Environmental Toxicology, Brisbane, Queensland, 4108, Australia. firstname.lastname@example.org
This study was undertaken to examine changes in Zn and Cu homeostasis in the liver and kidney of rats caused by cadmium (Cd) or lipopolysaccharide (LPS) administration. Twenty-five male, 7- to 8-week-old Wistar rats were divided into five groups: saline only treatment, saline treatment and food deprivation, exposure to a single dose of Cd, exposure to LPS alone, and exposure to Cd + LPS. Changes in plasma nitrate concentrations and hepatic and renal Zn and Cu contents were measured together with urinary excretion rates for the metals and nitrate on 3 consecutive days: 24 h before treatment and 24 and 48 h after treatments. Cd exposure alone for 48 h caused a nearly 2-fold increase in plasma nitrate levels with no changes in urinary nitrate excretion whereas LPS treatment caused plasma nitrate levels to increase by 10-fold and urinary nitrate excretion to increase by 4-fold. Administration of LPS 24 h after Cd exposure caused a 10-fold increase in plasma nitrate concentrations and a 100-fold increase in urinary nitrate excretion compared to the rates prior to LPS administration. These results indicate a synergistic interaction between Cd and LPS toxicity. Cd exposure also caused a marked increase in hepatic Zn levels, but LPS did not cause any changes in hepatic Zn or Cu content. In sharp contrast, both Zn and Cu contents were decreased in the kidneys by 16 and 36% in animals exposed to Cd or LPS. A correlation analysis of measured variables reveals that renal Cu contents were inversely associated with plasma nitrate concentrations while urinary Cu excretion on day 3 showed a strong positive correlation with both urinary nitrate and Cd excretions on the same day. A linear regression analysis shows 20% of the variation in urinary Cu excretion was associated with urinary Cd excretion on the same day. It is concluded that reductions in renal Cu contents caused by Cd or LPS administration may be a result of Cd and NO displacement of Cu previously bound to metallothionein. Copyright 2000 Academic Press.
PMID: 10944428 [PubMed - indexed for MEDLINE]