Urinary Porphyrin Excretion in Neurotypical and Autistic Children

James S. Woods; Sarah E. Armel; Denise I. Fulton; Jason Allen; Kristine Wessels; P. Lynne Simmonds; Doreen Granpeesheh; Elizabeth Mumper; J. Jeffrey Bradstreet; Diana Echeverria; Nicholas J. Heyer; James P.K. Rooney

Disclosures

Environ Health Perspect. 2010;118(10):1450-1457. 

In This Article

Abstract and Introduction

Abstract

Background: Increased urinary concentrations of pentacarboxyl-, precopro- and copro-porphyrins have been associated with prolonged mercury (Hg) exposure in adults, and comparable increases have been attributed to Hg exposure in children with autism (AU).
Objectives: This study was designed to measure and compare urinary porphyrin concentrations in neurotypical (NT) children and same-age children with autism, and to examine the association between porphyrin levels and past or current Hg exposure in children with autism.
Methods: This exploratory study enrolled 278 children 2–12 years of age. We evaluated three groups: AU, pervasive developmental disorder-not otherwise specified (PDD-NOS), and NT. Mothers/caregivers provided information at enrollment regarding medical, dental, and dietary exposures. Urine samples from all children were acquired for analyses of porphyrin, creatinine, and Hg. Differences between groups for mean porphyrin and Hg levels were evaluated. Logistic regression analysis was conducted to determine whether porphyrin levels were associated with increased risk of autism.
Results: Mean urinary porphyrin concentrations are naturally high in young children and decline by as much as 2.5-fold between 2 and 12 years of age. Elevated copro- (p < 0.009), hexacarboxyl- (p < 0.01) and pentacarboxyl- (p < 0.001) porphyrin concentrations were significantly associated with AU but not with PDD-NOS. No differences were found between NT and AU in urinary Hg levels or in past Hg exposure as determined by fish consumption, number of dental amalgam fillings, or vaccines received.
Conclusions: These findings identify disordered porphyrin metabolism as a salient characteristic of autism. Hg exposures were comparable between diagnostic groups, and a porphyrin pattern consistent with that seen in Hg-exposed adults was not apparent.

Introduction

Porphyrins are formed as intermediates in the biosynthesis of heme, a process that proceeds in essentially all eukaryotic tissues. In humans and other mammals, porphyrins with 8,7,6,5, and 4 carboxyl groups are commonly formed in excess of that required for heme biosynthesis and are excreted in the urine in a well-established pattern (Bowers et al. 1992; Woods et al. 1993). In previous studies we described specific changes in the urinary porphyrin excretion pattern (porphyrin profile) associated with prolonged exposure to mercury (Hg) in either organic or elemental forms (Pingree et al. 2001a; Woods et al. 1991, 1993). These changes are characterized by dose- and time-related increases in urinary concentrations of pentacarboxyl (5-carboxyl) and copro- (4-carboxyl) porphyrins and also by the appearance of precoproporphyrin, an atypical porphyrin [molecular weight (mw) = 668] that elutes on high-performance liquid chromatography (HPLC) prior to coproporphyrin (mw = 655) (Woods et al. 1991). The potential utility of these porphyrin changes as a biomarker of Hg exposure and body burden in adults with occupational exposure to elemental mercury (Hg0) has been described (Bowers et al. 1992; Gonzalez-Ramirez et al. 1995; Woods 1995; Woods et al. 1993)

Autism (AU), or autistic spectrum disorder (ASD), represents a serious neurodevelopmental disorder that afflicts as many as 1 in 110 children in the United States (Rice 2009). Although genetic factors likely play a principal role in the etiology of autism, a number of studies suggest that environmental exposures, occurring especially at critical periods of neurological development, may trigger events etiologic in AU/ASD among some children. In this respect, several reports (Kern et al. 2007; Mutter et al. 2005; Windham et al. 2006) have implicated prenatal and/or postnatal Hg exposure as associated with autism, in terms of frequency of exposure as well as total body burden. Notably, important mechanistic and toxicokinetic distinctions between different forms of Hg (Burbacher et al. 2005) or in child-specific factors (Faustman et al. 2000) that might affect susceptibility to Hg in autism remain to be fully considered in studies of this association. Nonetheless, some of the neuropsychiatric disturbances associated particularly with Hg0 exposure, such as cognition and communication deficits, sensory dysfunction, and impaired motor coordination, are notably similar to those observed in autism and ASD (Echeverria et al. 1998; Kolevzon et al. 2007).

In this context, Nataf et al. (2006) reported that a majority of > 100 French children with clinically confirmed autism displayed a urinary porphyrin excretion pattern comparable with that which we have observed in adult subjects with occupational Hg0 exposure and, moreover, that elevated porphyrin levels in these autistic children declined after chelation treatment, also comparable with that seen in occupationally exposed adults (Gonzalez-Ramirez et al. 1995; Woods et al. 1993). Similar findings have been reported among autistic children in the United States (Geier and Geier 2007) and Australia (Austin and Shandley 2008). Although Hg levels or exposure histories of the children involved in those studies were not reported, the precise change in the porphyrin excretion pattern that we observed in association with occupational Hg0 exposure in adult subjects implies that exposure to Hg may underlie this response among at least a subset children with autism. A principal concern with respect to these findings, however, is that urinary porphyrin levels in autistic children were commonly evaluated in relation to porphyrin concentrations for older control children or adults, which potentially could be misleading in light of finding that urinary porphyrin concentrations vary substantially with age among children and adolescents (Woods et al. 2009b). Moreover, no reference ranges for all typically excreted porphyrins for children < 8 years of age are currently available. Of additional concern is the common attribution in those studies of elevated porphyrins levels observed among autistic children to increased metal body burden when, in fact, direct measures of metal exposure were not reported.

We undertook the present exploratory study to address several issues associated with the use of urinary porphyrin changes as a diagnostic biomarker of Hg exposure among children and, in particular, those with autism. As the first objective, we measured urinary porphyrin concentrations for neurotypical (NT) children between 2 and 12 years of age against which porphyrin levels in same-age autistic children could be compared. Additionally, we sought to determine if differences in urinary porphyrin levels existed between NT and autistic children of the same age and, if so, if they were consistent with recent Hg exposure as assessed by urinary Hg levels and/or past Hg exposure determined from information acquired online at the time of registration.

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