Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case–control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case–control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose–effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), δ-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.

/pdf/environmental-toxicants-and-autism-spectrum-disorders-a-4p1z1vfehd.pdf

Environmental toxicants and autism spectrum disorders: a systematic review

Purpose of reviewThis review presents a rationale and evidence for contributions of environmental influences and environmentally vulnerable physiology to autism spectrum disorders (ASDs).Recent findingsRecent studies suggest a substantial increase in ASD prevalence above earlier Centers for Disease

/pdf/contributions-of-the-environment-and-environmentally-2qbxot6pv6.pdf

Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders

Peripheral-type" benzodiazepine receptors arelocalized totheouter mitochondrial membrane. Wehave identified potent competitive inhibitors ofthese receptors and purified themfromhumanblood andfromseveral ratorgans. TLC analysis ofthepurified inhibitor fromerythrocytes displays asingle peakofinhibitory activity withanabsorbance spectrum identical tohemin. Alloftheinhibitory activity in extracts ofseveral tissues canbeaccounted forbytheir porphyrin andmetalloporphyrin content. Pureheminand protoporphyrin IXcompetitively inhibit mitochondrial benzo- diazepine binding with K1values of41and15nM,respectively, andareless active byafactor of1000atcentral-type benzo- diazepine receptors. Thus, porphyrins appear tobeendoge- nousligands formitochondrial benzodiazepine receptors. Theanxiolytic effects ofbenzodiazepines aremediated bya "central" benzodiazepine receptor, located primarily inthe brain. However, manybenzodiazepines bindwithhigh af- finity toa"peripheral-type" receptor found innumerous

Porphyrins areendogenous ligands forthemitochondrial (peripheral-type ) benzodiazepine receptor

Toxicology and applied pharmacology

Biomarkers of environmental toxicity and susceptibility in autism

https://healthwyze.org/archive/porphyrinuria_childhood_autistic_disorder.pdf

Porphyrinuria in childhood autistic disorder: implications for environmental toxicity.

Background : Urinary metabolite measurements are often normalized to levels of the ubiquitous metabolite creati- nine (CRT) to take account of variations in fl export. Following CRT normalization, excesses of porphyrins and isoprostanes have been reported in the urines of children with neurodevelopmental disorders. It was suggested ( Whiteley et al. , 2006 , Pediatr. Int. 2006; 48 : 292 - 297) that urinary CRT levels may be depressed in children with autism spectrum disorders. This prompted re-evaluation of CRT levels in such children. Methods : First matinal urinary CRT levels were compared between subjects in different diagnostic categories includ- ing autistic disorder, pervasive developmental disorder not otherwise specifi ed (PDD-NOS) and hyperactivity, before and after correction for age and gender. A larger reference group, consisting of subjects with unrelated disorders and Asperger disorder, with no reported porphyrin excess, was also compared to the group with autistic disorder, both for CRT and for porphyrin (coproporphyrin, COPRO) excess. Results : No signifi cant difference in CRT was observed between any of the categories analyzed, also when corrected for age and gender. In contrast, urinary COPRO levels were signifi cantly higher in autistic disorder versus reference groups, either when expressed as absolute values (independent of CRT levels) or when normalized to CRT. Conclusions : These data do not support a systematic reduction in urinary CRT levels in subjects with autism spectrum disorders including autistic disorder and PDD-NOS. Urinary COPRO excess in autistic disorder was not associated with or consequent upon urinary CRT defi ciency. Differences between affected and control subjects in age and sampling time, as reported by Whiteley et al. , may underlie the apparent CRT reduction.

Corinne Skorupka

Papers

Porphyrinuria in childhood autistic disorder: implications for environmental toxicity.

Porphyrinuria in childhood autistic disorder is not associated with urinary creatinine deficiency