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Prenatal exposure to phthalates, maternal oxidative stress, and early childhood neurobehavior: a pathway modeling
Devyn L Cotter1, Mengling Liu2, Yuyan Wang2
1Department of Child and Adolescent Psychiatry, New York University Grossman School of Medicine, New York, NY, USA.
Insights
Prenatal exposure to di-2-ethylhexyl phthalate (DEHP) is linked to maternal oxidative stress and behavioral issues in male children. Oxidative stress did not mediate this association, suggesting other pathways for DEHP neurotoxicity.
Area of Science:
- Environmental Health
- Neuroscience
- Toxicology
Background:
- Phthalates, such as di-2-ethylhexyl phthalate (DEHP), are endocrine disruptors and neurotoxicants.
- Prenatal DEHP exposure is associated with adverse neurodevelopmental and neuropsychiatric outcomes.
- Maternal oxidative stress may be a mechanism underlying DEHP neurotoxicity.
Purpose of the Study:
- To investigate the association between prenatal DEHP exposure, maternal lipid peroxidation, and neurobehavioral outcomes in children.
- To examine the potential mediating role of maternal oxidative stress in the relationship between DEHP exposure and child behavior.
- To assess sex differences in these associations.
Main Methods:
- The study analyzed data from the New York University Children's Health and Environment Study.
- Prenatal DEHP exposure and maternal lipid peroxidation were measured via maternal urinary samples.
- Child behavior (internalizing/externalizing problems) was assessed at age 2 using the CBCL 1½-5, and neonatal BDNF was measured.
Main Results:
- Prenatal DEHP exposure was positively associated with maternal lipid peroxidation.
- DEHP exposure was linked to increased behavioral problems in male children, but not to BDNF levels in either sex.
- Maternal lipid peroxidation was not associated with BDNF or child behavioral problems.
Conclusions:
- Prenatal DEHP exposure is associated with maternal oxidative stress and behavioral problems in male children.
- Maternal oxidative stress does not mediate the observed association between DEHP and behavioral problems.
- Further research is needed to explore endocrine, metabolic, and epigenetic pathways in DEHP neurotoxicity.
Objective:
Phthalates are recognized endocrine disruptors and emerging neurotoxicants. Prenatal exposure to di-2-ethylhexyl phthalate (DEHP) has been linked to adverse neurodevelopmental and neuropsychiatric outcomes, and maternal oxidative stress may play a mechanistic role in prenatal DEHP's neurotoxicity.
Materials And Methods:
Participants were drawn from the New York University Children's Health and Environment Study. Prenatal DEHP exposure and maternal lipid peroxidation were assessed using repeated creatinine-adjusted maternal urinary measurements across pregnancy, collected from January 2016-April 2020. Neonatal brain-derived neurotrophic factor (BDNF) was measured in cord serum (N = 337), and internalizing and externalizing problems were assessed at an average age of 2 years using the Child Behavior Checklist for Ages 1.5-5 (CBCL 1½-5) (N = 824). DEHP metabolites (mEHHP; mEOHP; mECPP) were averaged across pregnancy, and cumulative lipid peroxidation biomarkers (8-iso-PGF2α; 15-PGF2α; 8,15-PGF2α; MDA) were estimated using area-under-the-curve values from linear mixed-effects spline models. Partial least squares path modeling evaluated direct and indirect associations using latent constructs for DEHP exposure, lipid peroxidation, CBCL 1½-5, and socioeconomic status; other covariates were modeled as single variables. Sex differences were assessed using bootstrapping and sex-stratified models, adjusting for maternal and child age, parity, pre-pregnancy body mass index, cotinine exposure, and socioeconomic status.
Results:
Prenatal DEHP exposure was positively associated with maternal lipid peroxidation in all models (β's = 0.11-0.27). Sex-stratified analyses showed that prenatal DEHP exposure was positively associated with CBCL 1½-5 in male children only (β = 0.11), but not with BDNF in either sex. Maternal lipid peroxidation was not associated with BDNF or CBCL 1½-5 in either sex.
Conclusion:
Prenatal DEHP exposure is associated with maternal oxidative stress and total behavioral problems in male children only, but maternal oxidative stress does not mediate these relationships. Alternative upstream mechanisms may underlie both maternal oxidative stress and neurobehavioral outcomes. Future studies should investigate endocrine, metabolic, and epigenetic pathways to clarify DEHP neurotoxicity.
