Sex-dependent vulnerability to early-life phthalates exposure and autism spectrum disorders: a systematic review

Abstract

Background Autism spectrum disorder (ASD) is a neurodevelopmental condition characterised by restricted and repetitive behaviours (ICD-11) and severe and persistent difficulties in social interaction and communication. A marked male predominance has consistently been reported, with ASD being three times more common among boys than girls, although the biological mechanisms underlying this sex difference remain unknown. Physical and chemical stressors occurring during critical windows of development may alter foetal and infant physiology and interfere with neurodevelopmental trajectories. Among these stressors, endocrine-disrupting chemicals (EDCs), including phthalates, have been proposed as potential environmental contributors to neurodevelopmental vulnerability. In this systematic review, we examined whether early-life exposure to phthalates may be associated with sex-specific vulnerability to ASD and autistic traits. Methods The systematic review was conducted in accordance with the PRISMA guidelines and followed a PECO framework. The target population included human children of both sexes, ranging from early childhood to adolescence. Exposures of interest included prenatal and/or early-life exposure to phthalates, assessed through biological matrices during prenatal and/or postnatal periods. Eligible outcomes included ASD and autistic-like traits assessed using validated diagnostic or screening tools. The review was registered in PROSPERO (CRD420261438630). Results A total of 18 studies were included. Phthalates exposure was assessed across a broad developmental window, ranging from the preconception period to 8 years of age. Urinary biomarkers represented the primary method for assessing chemical exposure, while a smaller proportion of studies also relied on blood samples. Sample size ranged from 77 to 3,220, and the age at assessment of autistic traits or ASD-related outcomes ranged from 18 months to 15 years. The Social Responsiveness Scale (SRS) was the most frequently used instrument for assessing autistic traits, followed by the Autism Diagnostic Observation Schedule (ADOS). Conclusion Prenatal exposure to phthalates, especially during early and mid-gestation, appears to be associated with subtle increases in autistic traits, with some evidence suggesting greater susceptibility among boys, particularly in relation to MBP, MEP, and DEHP-related metabolites. However, evidence remains limited and heterogeneous, and current findings require further confirmation. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/home, PROSPERO CRD420261438630.