Di-(2-Ethylhexyl) Phthalate and Autism Spectrum Disorders

Abstract

ASDs (autism spectrum disorders) are a complex group of neurodevelopment disorders, still poorly understood, steadily rising in frequency and treatment refractory. Extensive research has been so far unable to explain the aetiology of this condition, whereas a growing body of evidence suggests the involvement of environmental factors. Phthalates, given their extensive use and their persistence, are ubiquitous environmental contaminants. They are EDs (endocrine disruptors) suspected to interfere with neurodevelopment. Therefore they represent interesting candidate risk factors for ASD pathogenesis. The aim of this study was to evaluate the levels of the primary and secondary metabolites of DEHP [di-(2-ethylhexyl) phthalate] in children with ASD. A total of 48 children with ASD (male: 36, female: 12; mean age: 11±5 years) and age- and sex-comparable 45 HCs (healthy controls; male: 25, female: 20; mean age: 12±5 years) were enrolled. A diagnostic methodology, based on the determination of urinary concentrations of DEHP metabolites by HPLC-ESI-MS (HPLC electrospray ionization MS), was applied to urine spot samples. MEHP [mono-(2-ethylhexenyl) 1,2-benzenedicarboxylate], 6-OH-MEHP [mono-(2-ethyl-6-hydroxyhexyl) 1,2-benzenedicarboxylate], 5-OH-MEHP [mono-(2-ethyl-5-hydroxyhexyl) 1,2-benzenedicarboxylate] and 5-oxo-MEHP [mono-(2-ethyl-5-oxohexyl) 1,2-benzenedicarboxylate] were measured and compared with unequivocally characterized, pure synthetic compounds (>98%) taken as standard. In ASD patients, significant increase in 5-OH-MEHP (52.1%, median 0.18) and 5-oxo-MEHP (46.0%, median 0.096) urinary concentrations were detected, with a significant positive correlation between 5-OH-MEHP and 5-oxo-MEHP (rs = 0.668, P<0.0001). The fully oxidized form 5-oxo-MEHP showed 91.1% specificity in identifying patients with ASDs. Our findings demonstrate for the first time an association between phthalates exposure and ASDs, thus suggesting a previously unrecognized role for these ubiquitous environmental contaminants in the pathogenesis of autism.

Phthalate exposure and childrens neurodevelopment: A systematic review

“…In a cross-sectional study, Kim et al (2009) reported an inverse association between childhood MEHP and MEOP and teacher-rated ADHD scores and thus more ADHD symptoms. Using a case-control design, Testa et al (2012) found a positive association between prenatal MEHP and autism spectrum disorder diagnosis.…”

“…However, selection bias is only problematic if it is dependent on both exposure and outcome (Oleckno 2008), and thus the possibility of bias is minor. One of the eleven studies was a case-control study (Testa et al, 2012); therefore, selection of a representative control group is essential to ensure internal validity (Oleckno, 2008). Testa et al used 45 randomly selected age-and gender-comparable outpatients as their control group, and thus, the possibility of selection bias is minimized.…”

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

“…Higher urinary concentrations in autistic children [105]. Decreased Diethylhexyl Phthalate glucuronidation in autistic children [106].…”

Combined arsenic and di-(2-ethylhexyl) phthalate exposure elicits responses in brain ATPases different from hepatic and renal activities in rats

“…Environmental contaminants like arsenic and DEHP have been implicated in some neuropathological conditions (Testa et al, 2012;Siniscalco et al, 2013;Akyuzlu et al, 2014;Manivannan et al, 2015). There are also growing concerns about the adverse effects of toxicants on neurodevelopment (Kim et al, 2009;XiuJuan et al, 2013).…”