Neurodevelopmental effects of prenatal co-exposure to heavy metals and phthalates

Abstract

BACKGROUND AND AIM: There is a continuously growing evidemce on the neurodevelopmental effects of co-exposure to heavy metals and plasticisers, but also a lack of mechanistic interpretation. METHODS: Phthalate and heavy metals (Pb and Hg) prenatal exposure was determined measuring 11 phthalate metabolites in urine, Pb in blood and Hg in hair of (n=149) mothers during the third trimester of pregnancy (prenatal exposure) and from their children at the 24th month of age (postnatal exposure). Urine untargeted metabolomics analysis was also carried out in a Thermo Orbitrap LC/MS-MS. Psychomotor development was assessed in children at the age of 2 years using the Bayley Scale. Associations were investigated using the linkage disequilibrium method of EWAS, while pathway analysis was mapped with the Mass Profiler Pro (Agilent Technologies). RESULTS:Child motor development was inversely associated with natural log concentrations of 3OH-MnBP (log10p=1.6), 5OH-MEHP (log10p=1.9), and the sum of DEHP (log10p=1.7) and DnBP (log10p=1.7) metabolites, in the urine, as well as the Pb (log10p=2.3) in blood and the Hg (log10p=1.9) in hair collected from mothers. With regard to post-natal exposure, the only statistically significant associated association was the inverse correlation of Hg (log10p=1.9) in hair and cognitive functions for females. Metabolic pathway analysis revealed that alterations in selected phthalates urine metabolites, are related to the tricarboxylic acid (TCA) cycle, suggesting impaired mitochondrial respiration, which is central to energy metabolism and cellular signalling. The latter is enhanced by the oxidative stress induced by heavy metals. This defective mitochondrial energy production during the process of fetus formation and development is reflected in early life neurodevelopment. CONCLUSIONS:The key finding of the study is that although phthalates and metals affect mitochondrial respiration through different mechanisms (endocrine disruption and oxidative stress respectively), this synergistic effect is essential for the deployment of neurodevelopmental defects. KEYWORDS: Neurodevelopmental outcomes, Phthalates, Heavy metals; exposome, metabolomics