Gestational Exposure to Phthalates and Phthalate Replacements in Relation to Neurodevelopmental Delays in Early Childhood

Abstract

Phthalates have been linked to changes in child neurodevelopment. However, sex-specificity has been reported inconsistently, and little is known about the impact of recent phthalate replacement chemicals. Our analysis included mother–child pairs (N = 274) from the PROTECT birth cohort in Puerto Rico. Phthalate metabolites were measured in multiple maternal urine collected during pregnancy. Neurodevelopment was measured at 6, 12, and 24 months of age using the Battelle Developmental Inventory-2nd edition (BDI), which provides scores for adaptive, personal-social, communication, motor, and cognitive domains. Multivariable linear regression was used to examine associations between phthalate metabolite concentrations and BDI scores, adjusting for maternal age, maternal education, child age, and specific gravity. Sex-specificity was assessed with sex X exposure interaction terms and stratified models. Results show that all five domains were significantly associated with mono-3-carboxypropyl phthalate (MCPP) at age 24 months, suggesting a holistic developmental delay related to this metabolite. Sex-specificity existed for all timepoints (p-interaction < 0.2), in general, showing stronger associations among boys. For example, metabolites of a recent phthalate replacement, di-2-ethylhexyl terephthalate (DEHTP), were differentially associated with the adaptive domain (boys −7.53%/IQR, 95% CI: −14.58, −0.48 vs. girls −0.85%/IQR, 95% CI: −5.08, 3.37), and the cognitive domain (boys −6.05%/IQR, 95% CI: −10.88, −1.22 vs. girls −1.93%/IQR, 95%CI: −4.14, 0.28) at 6 months. To conclude, gestational exposure to phthalates and phthalate replacements was associated with neurodevelopmental delay across multiple domains, with differences by sex and child age.

Perinatal and postnatal exposure to phthalates and early neurodevelopment at 6 months in healthy infants born at term

“…A recent study suggested that prenatal exposure to phthalates could be inversely associated with the MDI and PDI of infants, particularly in males, at 6 months ( 34 ). Other studies ( 35 – 40 ) showed a negative correlation between phthalate levels and neurodevelopment: in all cases a significant inverse associations between prenatal exposure to DBP and cognitive and psychomotor development was found.…”

“…The small number of subjects enrolled in the study is strictly dependant by the complexity of urine sampling in newborn during their very first days of life, which is especially true when conducting stratification by sex. Given this problem, even if the sample appears small, this study is one of the few European studies to assess exposure at this timepoint and, at the moment, one of the largest ( 34 – 39 ). COVID-19 disruption of study protocol affected timing and logistic of sampling collection.…”

“…Several studies reported effect modification for numerous neurodevelopmental outcomes depending on the sex of the child ( 34 – 40 ), We performed regression models stratifying population by sex.…”

Association between pre- and postnatal exposure to endocrine-disrupting chemicals and birth and neurodevelopmental outcomes: an extensive review

“…168) Studies conducted in different countries have shown that prenatal DEHP, DBP, monobutyl phthalate, dibutyl phthalate, DIBP, and butyl benzyl phthalate exposure is associated with decreased language, verbal, communication, personal-social, cognitive, and psychomotor development; lower IQ; and learning difficulties during childhood. 143,[169][170][171][172][173] A recent meta-analysis demonstrated a significant association between prenatal phthalate exposure and psychomotor outcomes in children. 164) However, some authors have highlighted the importance of altered sex-specific differences in infant and child neurodevelopment.…”

Association of Di(2-ethylhexyl) Terephthalate and Its Metabolites with Nonalcoholic Fatty Liver Disease: An Epidemiology and Toxicology Study

“…Additionally, DEHTP exposure may also affect the nervous system. Maternal exposure to DEHTP during pregnancy may be related to delayed neurodevelopment in multiple domains of infants . Urinary MECPTP concentration during pregnancy was associated with higher postpartum blood pressure …”