Autism Research Institute

Advances in Autism Research
compiled by Teresa Binstock for ARI
April 2008

Infections, pollutants, immunity

Humans have learned lessons from seals:  Immunity is weakened by intra-body pollutants. Cites 25-30 present findings of Peter Ross and colleagues, who describe how food-borne pollutants and intra-body pollutants impair immunity. Findings by Ross and colleagues (22-27) remarkably parallel many of the immune findings in autistic children. Given that intra-body pollutants impair immunity, we must be concerned that human breast milk and human umbilical cord blood contain pollutants and that organic food can reduce ingestion of pollutants. This section concludes with several cites illustrating an important principle: one "low dose" pollutant may have unfindable or "mild" effects whereas two or more "low dose" pollutants may have findable or more significant effects (29-32). Furthermore, every study wherein humans were screened for intrabody toxins has found a large number of intrabody pollutants in every person thus far tested (33).

The autism epidemic is not as "mysterious" as we're led to believe. Hereinbelow are citations that, in a prelimary way, explore relationships among pollutants, immunity, and infections.


1: Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders

Nicolson GL et al.
J Neurosci Res. 2007 Apr;85(5):1143-8.

We examined the blood of 48 patients from central and southern California diagnosed with autistic spectrum disorders (ASD) by using forensic polymerase chain reaction and found that a large subset (28/48 or 58.3%) of patients showed evidence of Mycoplasma spp. infections compared with two of 45 (4.7%) age-matched control subjects (odds ratio = 13.8, P < 0.001). Because ASD patients have a high prevalence of one or more Mycoplasma spp. and sometimes show evidence of infections with Chlamydia pneumoniae, we examined ASD patients for other infections. Also, the presence of one or more systemic infections may predispose ASD patients to other infections, so we examined the prevalence of C. pneumoniae (4/48 or 8.3% positive, odds ratio = 5.6, P < 0.01) and human herpes virus-6 (HHV-6, 14/48 or 29.2%, odds ratio = 4.5, P < 0.01) coinfections in ASD patients. We found that Mycoplasma-positive and -negative ASD patients had similar percentages of C. pneumoniae and HHV-6 infections, suggesting that such infections occur independently in ASD patients. Control subjects also had low rates of C. pneumoniae (1/48 or 2.1%) and HHV-6 (4/48 or 8.3%) infections, and there were no coinfections in control subjects. The results indicate that a large subset of ASD patients shows evidence of bacterial and/or viral infections (odds ratio = 16.5, P < 0.001). The significance of these infections in ASD is discussed in terms of appropriate treatment. (c) 2007 Wiley-Liss, Inc.
    PMID: 17265454


2. Autistic symptoms following herpes encephalitis

Ghaziuddin M, Al-Khouri I, Ghaziuddin N.
Eur Child Adolesc Psychiatry. 2002 Jun;11(3):142-6.

Autism is a childhood onset neurodevelopmental disorder characterized by reciprocal social deficits, communication impairment, and rigid ritualistic interests, with the onset almost always before three years of age. Although the etiology of the disorder is strongly influenced by genes, environmental factors are also important. In this context, several reports have described its association with known medical conditions, including infections affecting the central nervous system. In this report, we describe an 11-year-old Asian youngster who developed the symptoms of autism following an episode of herpes encephalitis. In contrast to previous similar reports, imaging studies suggested a predominant involvement of the frontal lobes. At follow-up after three years, he continued to show the core deficits of autism. This case further supports the role of environmental factors, such as infections, in the etiology of autism, and suggests that in a minority of cases, autistic symptoms can develop in later childhood.
    PMID: 12369775


3. Autistic syndrome with onset at age 31 years: herpes encephalitis as a possible model for childhood autism

Gillberg IC.
Dev Med Child Neurol. 1991 Oct;33(10):920-4.

The author describes a previously healthy man who contracted herpes encephalitis at the age of 31 years, and over the following months developed all the symptoms considered diagnostic of autism. This case report casts doubt on the notion of autism as an exclusively developmental disorder. It is suggested that temporal lobe damage may cause autism in some cases.
    PMID: 1743418


4. Onset at age 14 of a typical autistic syndrome. A case report of a girl with herpes simplex encephalitis

Gillberg C.
J Autism Dev Disord. 1986 Sep;16(3):369-75.
    PMID: 3558293


5. Acquired reversible autistic syndrome in acute encephalopathic illness in children

DeLong GR, Bean SC, Brown FR 3rd.
Arch Neurol. 1981 Mar;38(3):191-4.

    In seeking the neurologic substrate of the autistic syndrome of childhood, previous studies have implicated the medial temporal lobe or the ring of mesolimbic cortex located in the mesial frontal and temporal lobes. During an acute encephalopathic illness, a clinical picture developed in three children that was consistent with infantile autism. This development was reversible. It was differentiated from acquired epileptic aphasia, and the language disorder was differentiated aphasia. One child has rises in serum herpes simplex titers, and a computerized tomographic (CT) scan revealed an extensive lesion of the temporal lobes, predominantly on the left. The other two, with similar clinical syndromes, had normal CT scans, and no etiologic agent was defined. These cases are examples of an acquired and reversible autistic syndrome in childhood, emphasizing the clinical similarities to bilateral medial temporal lobe disease as described in man, including the Klüver-Bucy syndrome seen in postencephalitic as well as postsurgical states.
    PMID: 6162440


6. Elevated levels of measles antibodies in children with autism

Singh VK, Jensen RL.
Pediatr Neurol. 2003 Apr;28(4):292-4.

Virus-induced autoimmunity may play a causal role in autism. To examine the etiologic link of viruses in this brain disorder, we conducted a serologic study of measles virus, mumps virus, and rubella virus. Viral antibodies were measured by enzyme-linked immunosorbent assay in the serum of autistic children, normal children, and siblings of autistic children. The level of measles antibody, but not mumps or rubella antibodies, was significantly higher in autistic children as compared with normal children (P = 0.003) or siblings of autistic children (P <or= 0.0001). Furthermore, immunoblotting of measles vaccine virus revealed that the antibody was directed against a protein of approximately 74 kd molecular weight. The antibody to this antigen was found in 83% of autistic children but not in normal children or siblings of autistic children. Thus autistic children have a hyperimmune response to measles virus, which in the absence of a wild type of measles infection might be a sign of an abnormal immune reaction to the vaccine strain or virus reactivation.
    PMID: 12849883


7. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism

Singh VK, Lin SX, Newell E, Nelson C.
J Biomed Sci. 2002 Jul-Aug;9(4):359-64.

Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using serum samples of 125 autistic children and 92 control children, antibodies were assayed by ELISA or immunoblotting methods. ELISA analysis showed a significant increase in the level of MMR antibodies in autistic children. Immunoblotting analysis revealed the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control sera. This antibody specifically detected a protein of 73-75 kD of MMR. This protein band, as analyzed with monoclonal antibodies, was immunopositive for measles hemagglutinin (HA) protein but not for measles nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in autistic sera detected measles HA protein, which is unique to the measles subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism. Copyright 2002 National Science Council, ROC and S. Karger AG, Basel
    PMID: 12145534


8. Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism

Singh VK, Lin SX, Yang VC.
Clin Immunol Immunopathol. 1998 Oct;89(1):105-8.

    Considering an autoimmunity and autism connection, brain autoantibodies to myelin basic protein (anti-MBP) and neuron-axon filament protein (anti-NAFP) have been found in autistic children. In this current study, we examined associations between virus serology and autoantibody by simultaneous analysis of measles virus antibody (measles-IgG), human herpesvirus-6 antibody (HHV-6-IgG), anti-MBP, and anti-NAFP. We found that measles-IgG and HHV-6-IgG titers were moderately higher in autistic children but they did not significantly differ from normal controls. Moreover, we found that a vast majority of virus serology-positive autistic sera was also positive for brain autoantibody: (i) 90% of measles-IgG-positive autistic sera was also positive for anti-MBP; (ii) 73% of measles-IgG-positive autistic sera was also positive for anti-NAFP; (iii) 84% of HHV-6-IgG-positive autistic sera was also positive for anti-MBP; and (iv) 72% of HHV-6-IgG-positive autistic sera was also positive for anti-NAFP. This study is the first to report an association between virus serology and brain autoantibody in autism; it supports the hypothesis that a virus-induced autoimmune response may play a causal role in autism. Copyright 1998 Academic Press.
    PMID: 9756729


9. Possible immunological disorders in autism: concomitant autoimmunity and immune tolerance

Kawashti MI, Amin OR, Rowehy NG.
Egypt J Immunol. 2006;13(1):99-104.
http://www.eji.egyptscience.com/jan06/jan06-10.pdf

Autism is a pervasive developmental disorder that affect children early in their life. Immunological disorders is one of several contributing factors that have been suggested to cause autism. Thirty autistic children aged 3-6 years and thirty non-autistic psychologically-free siblings were studied. Circulating IgA and IgG autoantibodies to casein and gluten dietary proteins were detected by enzyme-immunoassays (EIA). Circulating IgG antibodies to measles, mumps and rubella vaccine (M.M.R) and cytomeglovirus were investigated by EIA. Results revealed high seropositivity for autoantibodies to casein and gluten: 83.3% and 50% respectively in autistic children as compared to 10% and 6.7% positivity in the control group. Surprisingly, circulating anti-measles, anti-mumps and anti-rubella IgG were positive in only 50%, 73.3% and 53.3% respectively as compared to 100% positivity in the control group. Anti-CMV IgG was positive in 43.3% of the autistic children as compared to 7% in the control group. It is concluded that, autoimmune response to dietary proteins and deficient immune response to measles, mumps and rubella vaccine antigens might be associated with autism, as a leading cause or a resulting event. Further research is needed to confirm these findings.
    PMID: 17974154


10. Autism and congenital cytomegalovirus
Stubbs EG, Ash E, Williams CP.
J Autism Dev Disord. 1984 Jun;14(2):183-9.

Two cases of congenital cytomegalovirus infection associated with autism are reported. The viral hypothesis of autism is discussed along with a brief review of the literature. Suggestions are made for future research.
    PMID: 6086566


11. Possible association between congenital cytomegalovirus infection and autistic disorder

Yamashita Y, Fujimoto C, Nakajima E, Isagai T, Matsuishi T.
J Autism Dev Disord. 2003 Aug;33(4):455-9.

We encountered seven children with symptomatic congenital cytomegalovirus (CMV) infection from 1988 to 1995, of whom two (28.6%) developed typical autistic disorder. Case 1: A boy born at 38 weeks' gestation with a birth weight of 3164 g showed generalized petechiae, hepatosplenomegaly, and positive serum CMV-specific IgM antibodies. He was profoundly deaf, mentally retarded, and exhibited a lack of eye contact, stereotyped repetitive play, and hyperactivity. Case 2: A boy delivered at 39 weeks gestation with a birthweight of 2912 g showed non-progressive dilatation of the lateral ventricles observed postnatally. CMV-specific IgM antibodies were positive and CMV-DNA in the urine was confirmed by PCR. The boy was mentally retarded but not deaf. He showed no interest in people and delayed speech development. Subependymal cysts were detected by cranial ultrasound after birth in both patients. This is the first report describing subependymal cysts and the later development of AD. Cranial magnetic resonance imaging revealed an abnormal intensity area in the periventricular white matter suggestive of disturbed myelination; however, no migration disorders were found in our patients. These findings suggest that the timing of injury to the developing brain by CMV may be in the third trimester in some patients with autistic disorder.
    PMID: 12959425


12. Brief report: autistic disorder in three children with cytomegalovirus infection

Sweeten TL, Posey DJ, McDougle CJ.
J Autism Dev Disord. 2004 Oct;34(5):583-6.

Previous research has identified a relationship between autistic disorder (autism) and specific congenital infections. Three cases of congenital or perinatal cytomegalovirus (CMV) infection occurring in association with autism are described. Hypothetical mechanisms relating congenital infection, such as CMV, to the development of autism are discussed. A better understanding of the immunologic response to certain congenital infections may provide important information pertaining to the pathophysiology and etiology of autism in vulnerable individuals.
    PMID: 15628611


13: High frequency of systemic mycoplasmal infections in Gulf War veterans and civilians with Amyotrophic Lateral Sclerosis (ALS)

Nicolson GL et al.
J Clin Neurosci. 2002 Sep;9(5):525-9.

The presence of systemic mycoplasmal infections in the blood of Gulf War veterans (n=8) and civilians (n=28) with Amyotrophic Lateral Sclerosis (ALS) and age matched controls (n=70) was investigated by detecting mycoplasma gene sequences with forensic Polymerase Chain Reaction (PCR) and back hybridization with a radiolabeled internal oligonucleotide probe. Almost all ALS patients (30/36 or approximately 83%) showed evidence of Mycoplasma species in blood samples, whereas <9% of controls had blood mycoplasmal infections (P<0.001). Using PCR ALS patients with a positive test for any mycoplasmal infection were investigated for the presence of M. fermentans, M. pneumoniae, M. hominis and M. penetrans in their blood. All Gulf War veterans with ALS were positive for M. fermentans, except one that was positive for M. genitalium. In contrast, the 22/28 civilians with detectable mycoplasmal infections had M. fermentans (13/22, 59%) as well as other Mycoplasama species in their blood, and two of the civilian ALS patients had multiple mycoplasma species (M. fermentans plus M. hominis). Of the few control patients that were positive, only two patients (2/70, 2.8%) were positive for M. fermentans (P<0.001). The results support the suggestion that infectious agents may play a role in the pathogenesis and/or progression of ALS, or alternatively ALS patients are extremely susceptible to systemic mycoplasmal infections.
    PMID: 12383408


14. Interactions among infections, nutrients and xenobiotics

Ilbäck NG, Friman G.
Crit Rev Food Sci Nutr. 2007;47(5):499-519.

During recent years there have been several incidents in which symptoms of disease have been linked to consumption of food contaminated by chemical substances (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD). Furthermore, outbreaks of infections in food-producing animals have attracted major attention regarding the safety of consumers, e.g., Bovine Spongiform Encephalitis (BSE) and influenza in chicken. As shown for several xenobiotics in an increasing number of experimental studies, even low-dose xenobiotic exposure may impair immune function over time, as well as microorganism virulence, resulting in more severe infectious diseases and associated complications. Moreover, during ongoing infection, xenobiotic uptake and distribution are often changed resulting in increased toxic insult to the host. The interactions among infectious agents, nutrients, and xenobiotics have thus become a developing concern and new avenue of research in food toxicology as well as in food-borne diseases. From a health perspective, in the risk assessment of xenobiotics in our food and environment, synergistic effects among microorganisms, nutrients, and xenobiotics will have to be considered. Otherwise, such effects may gradually change the disease panorama in society.
    PMID: 17558657


15.  Persistent toxic chemicals: more than Stockholm persistent organic pollutants

Bengtsson G.
J Epidemiol Community Health. 2002 Nov;56(11):833-4.
http://jech.bmj.com/cgi/content/full/56/11/833

Schafer and Kegley bring up the important issue of excessive chemicals exposure of children. However, they do not consider in depth the "cumulative and simultaneous exposures faced by children, (.) moving beyond the chemical-by-chemical approach of the past", as quoted from the US Environmental Protection Agency national agenda to protect children from environmental health threats. Existing evidence for contamination by many substances beyond those dealt with in the article calls for additional protective measures. These could include an extra margin of exposure by a factor of 10 to cover cumulation of chemicals, for adults and children alike.
    PMID: 12388574

 

16. Persistent toxic chemicals in the US food supply.

Schafer KS, Kegley SE.
J Epidemiol Community Health. 2002 Nov;56(11):813-7.
http://jech.bmj.com/cgi/content/full/56/11/813

Persistent organic pollutants (POPs) have spread throughout the global environment to threaten human health and damage ecosystems, with evidence of POPs contamination in wildlife, human blood, and breast milk documented worldwide. Based on data from the US Food and Drug Administration, this article provides a brief overview of POPs residues in common foods in the United States food supply. The analysis focuses on 12 chemical compounds now targeted for an international phase out under the Stockholm Convention on POPs. The available information indicates that POPs residues are present in virtually all categories of foods, including baked goods, fruit, vegetables, meat, poultry, and dairy products. Residues of five or more persistent toxic chemicals in a single food item are not unusual, with the most commonly found POPs being the pesticides DDT (and its metabolites, such as DDE) and dieldrin. Estimated daily doses of dieldrin alone exceed US Environmental Protection Agency and US Agency for Toxic Substances Disease Control reference dose for children. Given the widespread occurrence of POPs in the food supply and the serious health risks associated with even extremely small levels of exposure, prevention of further food contamination must be a national health policy priority in every country. Implementation of the Stockholm Convention will prevent further accumulation of persistent toxic chemicals in food. Early ratification and rapid implementation of this treaty should be an urgent priority for all governments.
    PMID: 12388566


17: Identifying and managing adverse environmental health effects: 5. Persistent organic pollutants

Abelsohn A et al.
CMAJ. 2002 Jun 11;166(12):1549-54.
http://www.cmaj.ca/cgi/content/full/166/12/1549

Concern and awareness is growing about the health effects of exposures to environmental contaminants, including those found in food. Most primary care physicians lack knowledge and training in the clinical recognition and management of the health effects of environmental exposures. We have found that the use of a simple history-taking tool - the CH2OPD2 mnemonic (Community, Home, Hobbies, Occupation, Personal habits, Diet and Drugs) - can help physicians identify patients at risk of such health effects. We present an illustrative case of a mother who is concerned about eating fish and wild game because her 7-year-old son has been found to have learning difficulties and she is planning another pregnancy. Potential exposures to persistent organic pollutants (POPs) and mercury are considered. The neurodevelopmental effects of POPs on the fetus are reviewed. We provide advice to limit a patient's exposure to these contaminants and discuss the relevance of these exposures to the learning difficulties of the 7-year-old child and to the planning of future pregnancies.
    PMID: 12074124


18: Levels of persistent organic pollutants in several child day care centers

Wilson NK, Chuang JC, Lyu C.
J Expo Anal Environ Epidemiol. 2001 Nov-Dec;11(6):449-58.
http://www.nature.com/jea/journal/v11/n6/pdf/7500190a.pdf

The concentrations of a suite of persistent organic chemicals were measured in multiple media in 10 child day care centers located in central North Carolina. Five centers served mainly children from low-income families, as defined by the federal Women, Infants, and Children (WIC) assistance program, and five served mainly children from middle-income families. The targeted chemicals were chosen because of their probable carcinogenicity, acute or chronic toxicity, or hypothesized potential for endocrine system disruption. Targeted compounds included polycyclic aromatic hydrocarbons (PAHs), pentachloro- and nonyl-phenol, bisphenol-A, dibutyl and butylbenzyl phthalate, polychlorinated biphenyls (PCBs), organochlorine pesticides, the organophosphate pesticides diazinon and chlorpyrifos, and the herbicide 2,4-dichlorophenoxyacetic acid (2,4D). Sampled media were indoor and outdoor air, food and beverages, indoor dust, and outdoor play area soil. Concentrations of the targeted compounds were determined using a combination of extraction and analysis methods, depending on the media. Analysis was predominantly by gas chromatography/mass spectrometry (GC/MS) or gas chromatography with electron capture detection (GC/ECD). Concentrations of the targeted pollutants were low and well below the levels generally considered to be of concern as possible health hazards. Potential exposures to the target compounds were estimated from the concentrations in the various media, the children's daily time-activity schedules at day care, and the best currently available estimates of the inhalation rates (8.3 m(3)/day) and soil ingestion rates (100 mg/day) of children ages 3-5. The potential exposures for the target compounds differed depending on the compound class and the sampled media. Potential exposures through dietary ingestion were greater than those through inhalation, which were greater than those through nondietary ingestion, for the total of all PAHs, the phenols, the organophosphate pesticides, and the organochlorine pesticides. Potential exposures through dietary ingestion were greater than those through nondietary ingestion, which were greater than those through inhalation, for those PAHs that are probable human carcinogens (B2 PAH), the phthalate esters, and 2,4D. For the PCBs, exposures through inhalation were greater than those through nondietary ingestion, and exposures through dietary ingestion were smallest. Differences in targeted compound levels between the centers that serve mainly low-income clients and those that serve mainly middle-income clients were small and depended on the compound class and the medium.
    PMID: 11791162


19. Early childhood determinants of organochlorine concentrations in school-aged children

Karmaus W et al.
Pediatr Res. 2001 Sep;50(3):331-6.

We investigated whether early childhood factors such as breast-feeding, parity, and smoking contribute to the variation of organochlorine compounds (OC: dichlorodiphenyldichloroethene, hexachlorobenzene, beta-hexachlorocyclohexane, and the sum of polychlorinated biphenyls including the congeners 101, 118, 138, 153, 170, 180, 183, and 187) at approximately 7 y of age. OC were measured in whole blood of 350 children. Pregnancy characteristics and the child's living conditions were gathered by questionnaires administered to the parents and interviews with the mother. Height and weight were determined during the medical examination. Exclusion of incomplete data and nonbiologic children of the mothers yielded a sample of 337 children. We applied regression analysis with indicator variables, controlling for confounders. No systematic association was detected for birth order or maternal smoking during pregnancy. The OC concentrations are diluted in children with a higher body mass index (>18 kg/m(2)). We found a strong, dose-dependent relationship between the duration of breast-feeding (none, 1-4 wk, 5-8 wk, 9-12 wk, >12 wk) and the concentration of all five OCs. Of the potential determinants analyzed, more of the variance of the OC concentration is accounted for by breast-feeding than by any other variable. Exclusive breast-feeding beyond 12 wk was associated with a doubling of OC whole blood concentration compared with bottle-fed children (dichlorodiphenyldichloroethene, 0.28 microg/L versus 0.55 microg/L; beta-hexachlorocyclohexane, 0.05 microg/L versus 0.14 microg/L; hexachlorobenzene, 0.14 microg/L versus 0.25 microg/L; sum of polychlorinated biphenyls, 0.25 microg/L versus 0.55 microg/L). These findings indicate that breast-feeding can lead to an extended duration of increased OC exposure in childhood.
    PMID: 11518819


20: Concentrations of organochlorine pollutants in mothers who gave birth to neonates with congenital hypothyroidism

Nagayama J, Kohno H, Kunisue T, Kataoka K, Shimomura H, Tanabe S, Konishi S.
Chemosphere. 2007 Jun;68(5):972-6.

We have investigated the effects of prenatal exposure to dioxin-like compounds (PCDDs, PCDFs and dioxin-like PCBs), PCBs and organochlorine pesticides (DDT, HCH, chlordane, HCB and their metabolites) on the incidence of congenital hypothyroidism and/or cretinism in Fukuoka, Japan from 2001 to 2004. Thirty-four positive neonates of the mass-screening for cretinism were classified into three groups by the pediatrician after the reevaluation of the serum TSH level, that is, negative in reevaluation group, hyper thyroid stimulating hormone (TSH) emia group and cretinism group. One-hundred and two negative neonates of the mass-screening were classified into the normal group. Concentrations of these organochlorine compounds in the breast milk of mothers, which were considered as the indicator of prenatal exposures to them, were gradually increased from the normal group to the cretinism group in the four groups and were around two times higher in the cretinism group than in the normal group. According to the case-control study adjusted for the parity and mother's age, odds ratios of PCBs, DDT and HCB were 10 (p=0.003), 10 (p=0.003) and 22 (p=0.004), respectively and in dioxin-like compounds, PCDFs showed the highest odds ratio, 9.8 (p=0.005). Based upon those findings, these compounds seemed play an important role in the incidence and/or causation of the cretinism.
    PMID: 17307219


21: Perchlorate and iodide in dairy and breast milk

Kirk AB et al.
Environ Sci Technol. 2005 Apr 1;39(7):2011-7.

Perchlorate inhibits iodide uptake and may impair thyroid and neurodevelopment in infants. Recently, we unambiguously identified the presence of perchlorate in all seven brands of dairy milk randomly purchased from grocery stores in Lubbock, TX. How widespread is perchlorate in milk? Perchlorate in 47 dairy milk samples from 11 states and in 36 human milk samples from 18 states were measured. Iodide was also measured in a number of the samples. Perchlorate was detectable in 81 of 82 samples. The dairy and breast milk means were, respectively, 2.0 and 10.5 microg/L with the corresponding maximum values of 11 and 92 microg/L. Perchlorate is present in virtually all milk samples, the average concentration in breast milk is five times higher than in dairy milk. Although the number of available measurements are few at this point, for breast milk samples with a perchlorate content greater than 10 microg/L, the iodide content is linearly correlated with the inverse of the perchlorate concentration with a r2 of >0.9 (n = 6). The presence of perchlorate in the milk lowers the iodide content and may impair thyroid development in infants. On the basis of limited available data, iodide levels in breast milk may be significantly lower than it was two decades ago. Recommended iodine intake by pregnant and lactating women may need to be revised upward.
    PMID: 15871231


 

Immunity and pollutants: lessons from seals etc


22: Impaired cellular immune response in harbour seals (Phoca vitulina) feeding on environmentally contaminated herring

De Swart RL, Ross PS, Timmerman HH et al.
Clin Exp Immunol. 1995 Sep;101(3):480-6.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1553226&blobtype=pdf

In a 2.5-year immunotoxicological study, two groups of captive harbour seals (Phoca vitulina) were fed herring from the heavily polluted Baltic Sea or from the relatively uncontaminated Atlantic Ocean. Blood samples were collected at regular intervals, and functional immunological parameters were monitored. T cell mitogen and mixed lymphocyte-induced proliferative responses of peripheral blood mononuclear cells (PBMC) obtained from seals fed Baltic herring were significantly reduced over the course of experiment. Upon immunization with rabies virus antigen (RV) and tetanus toxoid (TT), specific proliferative responses of PBMC from the seals fed Baltic herring were also significantly reduced. Impairment of T cell-mediated immune responses became especially apparent during the second year on the respective diets, and correlated significantly to 2,3,7,8-tetrachloro-dibenzo-p-dioxin toxic equivalent levels in blubber biopsies taken from the seals after 2 years on the respective diets. Humoral immune responses, including lipopolysaccharide (LPS)-induced lymphoproliferative responses, in vitro immunoglobulin production by PBMC, as well as RV-, TT-and poliovirus-specific serum antibody responses following immunization, remained largely unaffected. We conclude that suppression of the cellular immune response in the seals fed Baltic herring was induced by the chronic exposure to immunotoxic environmental contaminants accumulated through the food chain. Since cellular immune responses are known to be of crucial importance in the clearance of morbillivirus infections, these results suggest that environmental pollution-related immunosuppression may have contributed to the severity and extent of recent morbillivirus-related mass mortalities among marine mammals.
    PMID: 7664495 


23. Impaired cellular immune response in rats exposed perinatally to Baltic Sea herring oil or 2,3,7,8-TCDD

Ross PS et al.
Arch Toxicol. 1997;71(9):563-74.

While the immunotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been well established, the effects of complex environmental mixtures of polyhalogenated aromatic hydrocarbons (PHAHs) are poorly understood. Many PHAHs, including the polychlorinated-biphenyls (PCBs), -dibenzofurans (PCDFs), and dibenzo-p-dioxins (PCDDs), possess 'dioxin-like' activities, and accumulate in the aquatic food chain. Organisms occupying high trophic levels may therefore be exposed to concentrations which may present an immunotoxic risk. In this study, pregnant PVG rats were administered a daily oral dose of 1 ml of the following during pregnancy and lactation: (1) oil extracted from herring caught in the relatively uncontaminated Atlantic Ocean; (2) oil extracted from herring caught in the contaminated Blastic Sea; or (3) the Atlantic herring oil extract spiked with 2,3,7,8-TCDD. The daily intakes of aryl hydrocarbon (Ah)-receptor dependent toxic equivalents (TEQ) for mothers were 0.3 in the Atlantic group, 2.1 in the Baltic group, and 134 ng/kg body wt. in the 2,3,7,8-TCDD positive control group. Immune function and host resistance to rat cytomegalovirus (RCMV) were assessed in offspring aged 11, 25, 46 or 59 days. Rat pups in the positive control TCDD-spiked group exhibited immunosuppression characterized by reduced thymus weight and cellularity, reduced thymocyte and splenocyte proliferative responses to T-dependent mitogens in vitro, reduced virus-associated natural killer (NK) cell and specific antibody responses. While less pronounced, a similar pattern of effects was observed in the rat pups exposed only to the Baltic Sea herring oil. These immunotoxic effects were transient in both exposure groups, with a time-related recovery in immune function possibly due to the half-life of TCDD in rats and the waning exposure levels in the rapidly growing pups. We previously demonstrated that the same Baltic Sea herring led to impaired natural killer cell and T-lymphocyte function in harbour seals during the course of a long-term captive feeding study. The collective results of these studies in rats and seals indicate the immunotoxic potential of environmental mixtures at current levels in the aquatic environment, and suggest that the developing immune system of young mammals may be at particular risk.
    PMID: 9285039


24: Association between lymphocyte proliferation and polychlorinated biphenyls in free-ranging harbor seal (Phoca vitulina) pups from British Columbia, Canada

Levin M, De Guise S, Ross PS.
Environ Toxicol Chem. 2005 May;24(5):1247-52.

Recent pinniped die-offs have led to the speculation that persistent organic pollutants (POPs) are immunomodulatory, making individuals more susceptible to viral infections. Eighteen healthy harbor seal (Phoca vitulina) pups (aged 3-4 weeks) were live-captured from southern British Columbia, Canada, and maintained temporarily in captivity for an immunotoxicological assessment. The relationships between mitogen-induced peripheral blood lymphocyte proliferation and blubber concentrations of three major immunotoxic POP classes (the polychlorinated biphenyls [PCBs], polychlorinated dibenzo-p-dioxins [PCDDs], and the polychlorinated dibenzofurans [PCDFs]) were evaluated. A significant body weight-independent positive correlation was observed between both T-cell mitogen (phytohemagglutinin [PHA])- and B-cell mitogen (lipopolysaccharide [LPS])-induced lymphocyte proliferation and the blubber concentrations of total PCB. Best subset regression analysis revealed that total PCBs, and not total PCDD or total PCDF, explained 24 and 29% of the changes in both T-cell mitogen-and B-cell mitogen-induced lymphocyte proliferation, respectively. Further regression analysis performed on the PCB classes measured in this study showed that di-ortho PCBs accounted for 25 and 30% of the changes in both T-cell and B-cell lymphocyte proliferation, respectively. Results suggest that POPs, and PCBs in particular, are associated with changes in lymphocyte proliferation, something that could result in increased susceptibility to infections in harbor seal pups. Further research is needed to evaluate the relative roles of natural and contaminant-related influences on the immune system of marine mammals.
    PMID: 16111007


25: Contaminant-associated disruption of vitamin A and its receptor (retinoic acid receptor alpha) in free-ranging harbour seals (Phoca vitulina)

Mos L et al.
Aquat Toxicol. 2007 Mar 10;81(3):319-28. Epub 2007 Jan 14

Polychlorinated biphenyls (PCBs) have been associated with a number of toxic effects in marine mammals such as endocrine disruption and immunotoxicity that, in turn, are widely thought to have contributed to population level impacts including reproductive failure and outbreaks of disease. In this study, the dietary hormone vitamin A and expression levels of one of its receptors, retinoic acid receptor alpha (RARalpha), were used as biomarkers of PCB-associated health effects in harbour seals. Harbour seal pups (n=24) were live-captured in coastal British Columbia, Canada, and Washington State, USA, and sampled for whole blood (to obtain peripheral blood mononuclear cells, PBMCs) and blood plasma, as well as biopsies of blubber and skin. Concentrations of circulatory vitamin A (retinol) in plasma and stored vitamin A in blubber were negatively associated with blubber PCB concentrations (R=-0.518, p=0.013 and R=-0.645, p=0.009, respectively). However, vitamin A concentrations in skin, an important target tissue, remained constant, which likely reflects a compensatory transfer from blubber to maintain physiological functions. In addition, we characterized the harbour seal RARalpha, and investigated its expression levels as a potential biomarker in seals. RARalpha expression in blubber, but not on PBMCs, was elevated in more contaminated animals (R=0.580, p=0.009). This may represent a direct contaminant-related effect, or, a compensation for the contaminant-related disruption of (circulatory and/or blubber) hormone levels. Since vitamin A is critical to developmental, reproductive and immunological health, our observations of a contaminant-related disruption of its physiology in free-ranging seals may portend population level consequences. Vitamin A concentrations and RARalpha expression levels can therefore represent relevant and sensitive biomarkers of PCB-associated toxic effects in toxicological studies of marine mammals.
    PMID: 17287035


26. Contaminant-related suppression of delayed-type hypersensitivity and antibody responses in harbor seals fed herring from the Baltic Sea

Ross PS et al.
Environ Health Perspect. 1995 Feb;103(2):162-7.
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1519003&blobtype=pdf

Recent mass mortalities among several marine mammal populations have led to speculation about increased susceptibility to viral infections as a result of contaminant-induced immunosuppression. In a 2.5-year study, we fed herring from either the relatively uncontaminated Atlantic Ocean or the contaminated Baltic Sea to two groups of captive harbor seals and monitored immune function in the seals. Seals fed the contaminated fish were less able to mount a specific immunological response to ovalbumin, as measured by in vivo delayed-type hypersensitivity (DTH) reactions and antibody responses. The skin reaction to this protein antigen was characterized by the appearance of mononuclear cells which peaked at 24 hr after intradermal administration, characteristic of DTH reactions in other animals studied. These DTH responses correlated well with in vitro tests of T-lymphocyte function, implicating this cell type in the reaction. Aryl-hydrocarbon (Ah) receptor-dependent toxic equivalent (TEQ) profiles in blubber biopsies taken from the seals implicated polychlorinated biphenyls rather than dioxins or furans in the observed immunosuppression. Marine mammal populations currently inhabiting polluted coastal environments in Europe and North America may therefore have an increased susceptibility to infections, and pollution may have played a role in recent virus-induced mass mortalities.
    PMID:


27: Chemical and biological pollution contribute to the immunological profiles of free-ranging harbor seals

Mos L et al.
Environ Toxicol Chem. 2006 Dec;25(12):3110-7.

Polychlorinated biphenyls and other persistent organic pollutants have been associated with immunotoxicity and outbreaks of (infectious) disease in marine mammals by rendering them vulnerable to infection by pathogens such as viruses and bacteria. In an immunotoxicological study of free-ranging harbor seals (Phoca vitulina), we obtained samples of blood and blubber from seal pups that were live-captured from two remote and two near-urban sites in British Columbia, Canada, and Washington state, USA. Using these samples, we quantified hematology, innate immune function, adaptive immune function, and polychlorinated biphenyl accumulation. While controlling for confounding factors (age, sex, and condition), univariate correlations between phagocytosis (r2 = 0.30, p = 0.002), respiratory burst (r2 =0.45, p= 0.000), T-lymphocyte function (r2 = 0.16, p = 0.028), lymphocyte signaling (r2 = 0.17, p = 0.025), and lymphocyte counts (r2 = 0.29, p = 0.002), and polychlorinated biphenyl concentrations suggested chemical-associated immunotoxicity. Principal component analysis of immunological endpoints provided additional evidence of immunotoxic effects in seals. However, principal component analysis also identified a noncontaminant-related factor by distinguishing between seals inhabiting urban versus remote sites, with results being consistent with increased pathogen exposure. Elevated fecal coliform concentrations in water, and observations of terrestrial spill-over pathogens in local seals, further support the notion of biological pollution at these sites. Although our study highlights the role that environmental contaminants might play in rendering marine mammal populations vulnerable to disease through immunotoxicity, it also suggests that biological pollution represents an emerging conservation concern.
    PMID: 17220

 

Accessible Pollutants: A very incomplete miscellany


27: Possible impact of phthalates on infant reproductive health

Lottrup G et al.
Int J Androl. 2006 Feb;29(1):172-80.

Phthalates adversely affect the male reproductive system in animals, inducing hypospadias, cryptorchidism, reduced testosterone production and decreased sperm counts. Phthalate effects are much more severe after in utero than adult exposure. Little is known about human health effects. This study discusses two recent studies on perinatal phthalate exposure, which indicated that human testicular development might be susceptible to phthalates. One study analysed phthalate monoesters in breast milk and reproductive hormone levels in infants. Five of six phthalates [monoethyl-(MEP), monobutyl- (MBP), monomethyl- (MMP), mono-2-ethylhexyl- (MEHP) and mono-isononyl phthalate (MiNP)] showed correlation with hormone levels in healthy boys, which were indicative of lower androgen activity and reduced Leydig cell function. MEP and MBP were positively correlated with serum sex hormone-binding globulin (SHBG) levels. MMP, MEP, MBP, MEHP and MiNP were positively correlated with the LH/testosterone ratio. Another study found a reduction of the anogenital index (AGI) in infant boys with increasing levels of MBP, MEP, monobenzyl- and mono-isobutyl phthalate in maternal urine samples during late-pregnancy. Boys with small AGI showed a high prevalence of cryptorchidism and small genital size. Taken together these studies suggest an antivirilizing effect of phthalates in infants. Most of these findings are in line with animal observations. However, the possible effects of MEP appear to be limited to humans. This may be due to differences in exposure routes (inhalation and dermal absorption which circumvents liver detoxification in addition to oral) and metabolism, or this association could be spurious. As phthalates are produced as bulk chemicals worldwide, these new findings raise concern about the safety of phthalate exposure for pregnant women and infants.
   PMID: 16466537


28: Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age

Main KM et al
Environ Health Perspect. 2006 Feb;114(2):270-6.
http://www.ehponline.org/members/2005/8075/8075.pdf

Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. DESIGN: We obtained biologic samples from a prospective Danish-Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1-3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. RESULTS: All phthalate monoesters were found in breast milk with large variations [medians (minimum-maximum)]: mMP 0.10 (< 0.01-5.53 microg/L), mEP 0.95 (0.07-41.4 microg/L), mBP 9.6 (0.6-10,900 microg/L), mBzP 1.2 (0.2-26 microg/L), mEHP 11 (1.5-1,410 microg/L), miNP 95 (27-469 microg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001-0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21-0.323, p = 0.002-0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = -0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. CONCLUSIONS: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally.
   PMID: 16451866


29: Polybrominated diphenyl ethers, a group of brominated flame retardants, can interact with polychlorinated biphenyls in enhancing developmental neurobehavioral defects

Eriksson P, Fischer C, Fredriksson A.
Toxicol Sci. 2006 Dec;94(2):302-9. Epub 2006 Sep 15.

The present study shows that polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) can interact and enhance developmental neurobehavioral defects when the exposure occurs during a critical stage of neonatal brain development. PBDEs are used in large quantities as flame-retardant additives in polymers, especially in the manufacture of a great variety of electrical appliances, and textiles. In contrast to the well-known persistent compounds PCBs and DDT, the PBDEs have been found to increase in the environment and in human mother's milk. We have previously shown that low-dose exposure to environmental toxic agents such as PCB can cause developmental neurotoxic effects when present during a critical stage of neonatal brain development. Epidemiological studies indicate the adverse neurobehavioral impact of PCBs. Recently, we reported that neonatal exposure to PBDEs causes developmental neurotoxic effects. In the present study, 10-day-old Naval Medical Research Institute male mice were given one single oral dose of PCB 52 (1.4 micromol/kg body weight [bw]) + PBDE 99 (1.4 micromol), PCB 52 (1.4 micromol or 14 micromol), or PBDE 99 (1.4 micromol or 14 micromol). Controls received a vehicle (20% fat emulsion). Animals exposed to the combined dose of PCB 52 (1.4 micromol) + PBDE 99 (1.4 micromol) and the high dose of PCB 52 (14 micromol) or PBDE 99 (14 micromol) showed significantly impaired spontaneous motor behavior and habituation capability at the age of 4 and 6 months. The neurobehavioral defects were also seen to worsen with age in mice neonatally exposed to PCB 52 + PBDE 99.
    PMID: 16980691


30: Neonatal co-exposure to low doses of an ortho-PCB (PCB 153) and methyl mercury exacerbate defective developmental neurobehavior in mice

Fischer C, Fredriksson A, Eriksson P.
Toxicology. 2008 Feb 28;244(2-3):157-65. Epub 2007 Nov 19.

Epidemiological studies have shown a discrepancy between children in the Faeroe Islands and children in the Seychelles with regard to neuropsychological defects during early development. Both populations have a high consumption of MeHg-contaminated fish. The defective neuropsychological differences seen in children from the Faeroe Islands could be attributed to PCBs via the mother's dietary consumption of whale meat and blubber in addition to MeHg. We have previously reported that certain persistent environmental toxicants like PCBs, DDT and PBDEs can induce permanent developmental neurotoxic effects in mice when these agents are present during a critical period of the neonatal brain development. The present study investigates whether PCB 153 (an ortho-substituted PCB) can interact with MeHg to enhance developmental neurotoxic effects on spontaneous behavior and habituation. Neonatal NMRI male mice were exposed at 10 days of age to a single oral dose of one of the following doses: PCB 153 (1.4micromol/kg body weight), MeHg (0.08, 0.40, or 4.0mg/kg body weight), PCB 153 plus MeHg, or a vehicle (20% fat emulsion). Spontaneous behavior, habituation, and cognitive function were observed in 2- and 4-month-old mice. The present study demonstrates that an interaction from co-exposure to low doses of PCB 153 and MeHg enhances developmental neurotoxic effects. These effects are manifested as disrupted spontaneous behavior, lack of habituation, and reduced cognitive functions. These effects occur at doses within the same order of magnitude as reported for exposed children.
    PMID: 18155821


31: Coexposure of neonatal mice to a flame retardant PBDE 99 (2,2',4,4',5-pentabromodiphenyl ether) and methyl mercury enhances developmental neurotoxic defects

Fischer C, Fredriksson A, Eriksson P.
Toxicol Sci. 2008 Feb;101(2):275-85. Epub 2007 Nov 2.

Epidemiological studies indicate that exposure to environmental pollutants during early human development can have deleterious effects on cognitive development. The interaction between environmental pollutants is suggested as one reason for the observed defective neurological development in children from the Faeroe Islands as compared to children from the Seychelles. We have previously seen in mice that polychlorinated biphenyls (PCBs) can interact together with methyl mercury (MeHg), as well as PCB together with polybrominated diphenyl ether (PBDE 99) to exacerbate developmental neurotoxic effects when present during a critical period of neonatal brain development. PBDEs are a new class of global environmental contaminants. The present study shows that neonatal coexposure to PBDE 99 (0.8 mg/kg body weight) and MeHg (0.4 or 4.0 mg/kg body weight) can exacerbate developmental neurotoxic effects. These effects are manifested as disrupted spontaneous behavior, reduced habituation, and impaired learning/memory abilities. This is seen in the low dose range, where the sole compounds do no give rise to developmental neurotoxic effects. The effects seen are more than just additive. Furthermore, a significant effect of interaction was seen on the cholinergic nicotinic receptors in the cerebral cortex and hippocampus. This suggests that a mechanism for the observed cognitive defects is via the cholinergic system. Furthermore, PBDE can interact with MeHg causing developmental neurotoxic effects similar to those we previously have observed between PCB 153 + MeHg and PCB 52 + PBDE 99. This is of vital importance, as the levels of PBDEs are increasing in mother's milk and in the environment generally.
    PMID: 17982161


32: Proteomic evaluation of neonatal exposure to 2,2 ,4,4 ,5-pentabromodiphenyl ether

Alm H et al.
Environ Health Perspect. 2006 Feb;114(2):254-9.
http://www.ehponline.org/members/2005/8419/8419.html

Exposure to the brominated flame retardant 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) during the brain growth spurt disrupts normal brain development in mice and results in disturbed spontaneous behavior in adulthood. The neurodevelopmental toxicity of PBDE-99 has been reported to affect the cholinergic and catecholaminergic systems. In this study we use a proteomics approach to study the early effect of PBDE-99 in two distinct regions of the neonatal mouse brain, the striatum and the hippocampus. A single oral dose of PBDE-99 (12 mg/kg body weight) or vehicle was administered to male NMRI mice on neonatal day 10, and the striatum and the hippocampus were isolated. Using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE), we found 40 and 56 protein spots with significantly (p < 0.01) altered levels in the striatum and the hippocampus, respectively. We used matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF-MS) to determine the protein identity of 11 spots from the striatum and 10 from the hippocampus. We found that the levels of proteins involved in neurodegeneration and neuroplasticity (e.g., Gap-43/neuromodulin, stathmin) were typically altered in the striatum, and proteins involved in metabolism and energy production [e.g., alpha-enolase; gamma-enolase; ATP synthase, H+ transporting, mitochondrial F1 complex, beta subunit (Atp5b); and alpha-synuclein] were typically altered in the hippocampus. Interestingly, many of the identified proteins have been linked to protein kinase C signaling. In conclusion, we identify responses to early exposure to PBDE-99 that could contribute to persistent neurotoxic effects. This study also shows the usefulness of proteomics to identify potential biomarkers of developmental neurotoxicity of organohalogen compounds.
    PMID: 16451863


33. Tissue uptake of mercury is changed during the course of a common viral infection in mice

Frisk P, Molin Y, Ilbäck NG.
Environ Res. 2008 Feb;106(2):178-84.

Mercury (Hg) has been shown to have immunotoxic effects and to influence the severity of infection. However, the impact of infection on the normal Hg homeostasis in different target organs involved in the disease process has not been studied. In this study, Hg was measured through inductively coupled plasma-mass spectrometry (ICP-MS) in the intestine, serum, liver, and brain on days 3, 6, and 9 of coxsackievirus B3 (CVB3) infection in female Balb/c mice. The severity of the infection was assessed from clinical signs of disease and the number of virus particles in infected organs. CVB3 and gene expression of metallothionein 1 (MT1) was measured by reverse transcription-polymerase chain reaction (RT-PCR). Gene expression of MT1 increased and peaked on day 3 in the brain (93%, p<0.01) and liver (19-fold, p<0.01) and on day 6 in the intestine (seven-fold, p<0.01). This peak in MT1 in the liver and brain corresponded to the peak in virus numbers in these tissues. Hg in the intestine and serum tended to decrease on all days of infection. The maximum decrease, in comparison with non-infected mice, occurred in the intestine (78%, p<0.001) on day 9 and in serum (50%, p<0.05) on day 6. However, in the brain, Hg increased by 52% (p<0.05) on day 6. Hg went unchanged in the liver. An infection-induced increase of Hg in the brain but unchanged level in the liver may be due to the peak of virus replication and an associated infection-induced expression of MT1. Moreover, the decrease of Hg in serum and the intestine but a concomitant intestinal increase in MT1 on day 6 may reflect a flux and increased retention of Hg to infected organs such as the brain. The pathophysiological interpretation of these preliminary findings requires further research.
    PMID: 17888900


34. Infectious and immune factors in the pathogenesis of neurodevelopmental disorders: epidemiology, hypotheses, and animal models

Hornig M, Lipkin WI.
Ment Retard Dev Disabil Res Rev. 2001;7(3):200-10.

Both genetic and environmental factors contribute to the pathogenesis of a wide variety of neurodevelopmental disorders, including autism, mental retardation, and schizophrenia. Some heritable disorders approach 100% penetrance; nonetheless, even in these disorders, subtle aspects of clinical disease expression may be influenced by the environment. In other disorders with genetic influences, exogenous factors, and the timepoint(s) during nervous system development at which they are introduced, modulate expression of disease. Elucidation of the mechanisms guiding this intricate interplay between host response genes, environmental agents, and the neurodevelopmental context within which these interactions occur, is necessary to understand the continuum of clinical outcomes. This chapter will review the evidence that infectious and immune factors may contribute to the pathogenesis of neurodevelopmental disorders, describe an animal model of neurodevelopmental disorders based upon viral infection, identify processes by which neural circuitry may be compromised, and outline areas for future research. Copyright 2001 Wiley-Liss, Inc.
     PMID: 11553936


35. Borna disease virus infection of the neonatal rat: developmental brain injury model of autism spectrum disorders

Pletnikov MV, Moran TH, Carbone KM.
Front Biosci. 2002 Mar 1;7:d593-607.

Autism spectrum disorders (ASD) have been the focus of a great deal of research and clinical speculation. This intense interest relates to both the perplexing pathogenesis and devastating consequences of these disorders. One of the obstacles to understanding the pathogenesis of autism and its efficient treatment has been the paucity of animal models that could be used for hypotheses-driven mechanistic studies of abnormal brain and behavior development and for the pre-clinical testing novel pharmacological treatments. The present review provides a detailed analysis of a new animal model of ASD. This model utilizes neonatal Borna disease virus (BDV) infection of the rat brain as a unique experimental teratogen to study the pathogenesis of neurodevelopmental damage. For more than a decade, studies of the BDV animal model have yielded much insight into the pathogenic processes of abnormal brain development and resulting autistic-like behavioral abnormalities in rats. The most recent experiments demonstrate the utility of the BDV model for studying the pathophysiological mechanisms of the gene-environment interaction that determines differential disease outcomes and variability in responses to treatments.
    PMID: 11861216


36. Borna disease virus (BDV)-induced model of autism: application to vaccine safety test design

Carbone KM, Rubin SA, Pletnikov M.
Mol Psychiatry. 2002;7 Suppl 2:S36-7.
http://www.nature.com/mp/journal/v7/n2s/pdf/4001174a.pdf
    PMID: 12142944


37. Intra-body toxins: Nutrient depletion increases susceptibility.

Teresa Binstock
Appendix C, p307-316 in: Children with Starving Brains, 3rd edition, 2007.

Nutrients and Immunity
Autism, Pollution, and Nutrients: a Unifying Relationship
Defiling Sacredness: Pollutants in Cord Blood and Breast Milk

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