Next Article in Journal
Negligible Toxicokinetic Differences of Glyphosate by Different Vehicles in Rats
Next Article in Special Issue
Per- and Polyfluoroalkyl Substances and Breastfeeding as a Vulnerable Function: A Systematic Review of Epidemiological Studies
Previous Article in Journal
Advantages and Disadvantages of Electronic Cigarettes
Previous Article in Special Issue
Associations between Phthalate Exposure and Gestational Age at Delivery in a Diverse Pregnancy Cohort
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Toxics
Volume 11
Issue 1
10.3390/toxics11010065
toxics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Seonyoung Park
1,
Emily Zimmerman
2,
Gredia Huerta-Montañez
3,
Zaira Rosario-Pabón
3,
Carmen M. Vélez-Vega
4,
José F. Cordero
5,
Akram Alshwabekah
6,
John D. Meeker
1 and
Deborah J. Watkins
1,*
1
Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA
2
Department of Communication Sciences and Disorders, Northeastern University, Boston, MA 02115, USA
3
Department of Electrical and Computer Engineering, Northeastern University, Boston, MA 02115, USA
4
Department of Social Sciences, UPR Medical Sciences Campus, University of Puerto Rico Graduate School of Public Health, San Juan, PR 00936, USA
5
Department of Epidemiology and Biostatistics, University of Georgia, Athens, GA 30602, USA
6
Department of Civil and Environmental Engineering, Northeastern University, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Toxics 2023, 11(1), 65; https://doi.org/10.3390/toxics11010065
Submission received: 25 October 2022 / Revised: 1 January 2023 / Accepted: 2 January 2023 / Published: 11 January 2023
(This article belongs to the Special Issue Insights of Perinatal Endocrine Disruptors Exposure Influencing Maternal and Child Health)
Browse Figures
Versions Notes

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.

1. Introduction

Child neurodevelopmental delay refers to a delay in one or more neurodevelopmental domains—cognitive, adaptive, language, and motor skills [1]. The risk of neurodevelopmental delay in the United States was estimated at 4.7% among children of three to seven years of age between 2014 and 2016, even when excluding serious clinical disorders such as autism spectrum disorder or intellectual disability [2]. Early life neurodevelopmental delay is significant, not only because it contributes to rising health care costs and productivity costs, but because such a delay may evolve as a child grows [3]. Gestation is a particularly vulnerable period for environmental exposure because endocrine-disrupting chemicals can create an imbalance in hormones that play an important role in development, generate maternal oxidative stress, and dysregulate immune responses which may compromise fetal development. Alternatively, neurotoxic chemicals may directly affect the fetus by crossing the placenta, and the impacts may last until later in life. Establishing linkages between environmental exposures and neurodevelopmental delays will have great public health significance as many exposures can be modifiable through new interventions and policies at the local and federal levels.
Phthalates are chemicals widely used in the production of plastics and personal care products, in addition to many other applications. Thus, exposure to phthalates is ubiquitous in the general population. Phthalates may disrupt the thyroid signaling pathway [4], induce intracellular oxidant/antioxidant imbalance [5], break double-stranded DNA in human neurons [6], or alter brain structure [7], which may ultimately negatively affect fetal growth and brain development. In addition, phthalates are known to be estrogenic and anti-androgenic [8,9,10,11]. Studies have shown that phthalate exposures during gestation are associated with altered sex hormone levels of mothers [12,13,14,15,16], which have been linked to neurodevelopmental problems in the offspring [17,18,19].
Epidemiologic studies suggest that intrauterine phthalate exposure is linked to neurodevelopmental delay in early childhood (one year to school age), including cognitive and behavioral function [20,21,22,23]. However, findings are not fully conclusive and limited overlap exists across the neurodevelopmental domains assessed. In addition, developmental delay in early infancy in relation to phthalate exposure is not well understood, and inconsistent sex-specificity has been reported. Furthermore, the health effects of phthalate replacements such as di-2-ethylhexyl terephthalate (DEHTP) on child neurodevelopmental delay have not been addressed in observational studies even as exposure to these chemicals is increasing in the US [24].
To fill this knowledge gap, our study aimed to examine relationships between biomarkers of gestational exposure to phthalates, including a recent phthalate replacement chemical, and neurodevelopment across five domains (adaptive, personal-social, communication, motor, and cognitive domains) in children at 6, 12, or 24 months of age in Puerto Rico. We hypothesized that prenatal exposure to phthalates or phthalate replacements is associated with child neurodevelopmental delay from 6 to 24 months of age, and that sex-specificity exists in such relationships.

2. Materials and Methods

2.1. Study Participants

Participants were part of the ongoing prospective birth cohort, the PROTECT study in Puerto Rico, which was initiated in 2010. Women were recruited at approximately 14 ± 2 weeks of gestation and inclusion criteria were that they (1) were between 18 and 40 years old, (2) lived in the Northern karst region, (3) did not use oral contraceptives three months prior to pregnancy, (4) did not report major obstetrical or medical complications, and (5) did not use in vitro fertilization to achieve the pregnancy [25]. Prenatal urine samples were collected during study visits at approximately 18, 22, and 26 weeks of gestation, and demographic and socioeconomic information was collected through a series of detailed questionnaires [26]. At the time of this analysis, a total of 1576 PROTECT women had at least one prenatal phthalate metabolite measurement (Figure 1). The outcome measures of child neurodevelopment were collected by the Center for Research on Early Childhood Exposure and Development in Puerto Rico (CRECE), which began in 2016 to track children who were born to PROTECT mothers through the age of four years [27]. Among the PROTECT participants who (1) met the CRECE recruitment criteria, and (2) were still younger than four years old, 555 babies were enrolled in the CRECE cohort and followed up at multiple time points, including 6–8 months, 12 months, and 24 months. In this analysis, 274 children with neurobehavioral assessments from at least one timepoint were included. Fifteen children had assessments at all three timepoints, and 77 had assessments at two timepoints (Figure 1).
This study was approved by the research and ethics committees of the University of Michigan School of Public Health, Northeastern University, the University of Puerto Rico, and participating hospitals and clinics. Study participants received a full description of the study and provided full informed consent prior to participation.

2.2. Phthalate Metabolite Measurements

Phthalate metabolites were measured in maternal urine samples collected during each prenatal study visit. All samples were frozen at −80 °C and shipped on dry ice to the Center for Disease Control and Prevention for analysis. Urinary concentrations of 15 phthalate and two DEHTP metabolites were measured using solid-phase extraction HPLC-isotope dilution tandem mass spectrometry as previously described [28]. Measured phthalate metabolites were mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-benzyl phthalate (MBzP), monocarboxyoctyl phthalate (MCOP), mono-isononyl phthalate (MNP), mono-oxoisononyl phthalate (MONP), monocarboxynonyl phthalate (MCNP), mono (3-carboxypropyl) phthalate (MCPP), mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-3-hydroxybutyl phthalate (MHBP), mono- isobutyl phthalate (MiBP) and mono-2-hydroxy-iso-butyl phthalate (MHiBP) and two DEHTP metabolites, mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and mono-2-ethyl-5-hydroxyhexyl terephthalate (MEHHTP) [29]. Summary measures of phthalate parent compounds were calculated by adding the molar fractions of metabolites; MEHP, MEHHP, MEOHP and MECPP for ΣDEHP; MBP and MHBP for ΣDBP; MiBP and MHiBP for ΣDiBP; MECPTP and MEHHTP for ΣDEHTP. We then multiplied summary measures by the molecular weight of the primary metabolite for unit comparability (ng/mL); MEHP (278.348 g/mol) for ΣDEHP; MBP (222.24 g/mol) for ΣDBP; MiBP (222.24 g/mol) for ΣDiBP; MEHHTP (294.34 g/mol) for ΣDEHTP, as previously described [30]. Values below the limit of detection (LOD) were substituted by LOD divided by the square root of 2. This imputation method has been shown to produce nonbiased means and SDs when the percentage of samples below the LOD is low, and is justified because all phthalate metabolites in our analysis were detected in more than 70% of urine samples collected across the study visits [31]. This approach has also been applied in other studies leveraging urinary phthalate metabolite biomarkers [32,33,34]. To account for urinary dilution, specific gravity (SG) was measured using a handheld digital refractometer (Atago Co., Ltd., Tokyo, Japan) at the University of Puerto Rico Medical Sciences Campus at the time of the sample collection. Urinary concentrations were corrected for specific gravity using the following formula: Pc = P [SGm-1SGi-1], where Pc is the specific gravity-corrected concentration (ng/mL), P is the measured urinary concentration, SGm is the median specific gravity across the study population (1.019), and SGi is the specific gravity for each participant [28]. Previous studies show that one urinary phthalate measurement reflects very recent exposure, whereas averaging multiple repeated urinary measurements is a better characterization of exposure over time [30]. Therefore, geometric means of specific gravity-corrected phthalate metabolite levels across pregnancy were used in the analysis.

2.3. Neurobehavioral Assessments

We used the Battelle Developmental Index-2 Spanish edition (BDI-2) to evaluate children’s neurodevelopment at the age of 6 months, 12 months, or 24 months. The BDI-2 assesses age-specific neurobehavioral function across five domains—adaptive, cognitive, personal-social, communication, and motor—using structured, observational, and interview items [35].
Each domain consists of one or two “subdomains” and there are nine subdomains in total—self-care under the adaptive domain (ADP); adult interaction, and self-concept and social role under personal-social domain (PS); receptive communication and expressive communication under communication domain (COM); gross motor, and fine motor under motor domain (MOT); attention and memory, reasoning and academic skills, and perception and concepts under cognitive domain (COG) [35,36]. The BDI-2 yields a developmental quotient (DQ) score for each domain and a scaled score for each subdomain, and both the DQ score and scaled score are norm-based (mean of 100, SD of 15 for domain scores and mean of 10, SD of 3 for the subdomain). Lower DQ scores or scaled scores indicate a poorer performance in the corresponding domain or subdomain. BDI-2 total scores, composites of all the domain test information, were calculated by summing the scaled scores of all subdomains within each domain. Five domain DQ scores and nine subdomain scaled scores were used in the analysis, and scores at the three-time points were used separately to examine the association with prenatal phthalate exposures.

2.4. Statistical Analyses

Distributions of urinary exposure biomarkers and BDI-2 outcome measures were assessed prior to analysis. Urinary phthalate metabolite concentrations were natural log-transformed and BDI-2 scores were added as a continuous variable in regression models. The associations between urinary concentrations of phthalate and replacement metabolites and BDI-2 domain DQ scores and subdomain scaled scores were examined using multivariable regression models, adjusting for potential confounders. Separate models were used for each phthalate metabolite and each BDI-2 domain or subdomain score was measured at each time point. Additionally, the role of the child’s sex as an effect modifier was assessed by adding interaction terms of sex and urinary phthalate concentration in regression models. If evidence of an interaction between phthalate metabolites and sex on the BDI-2 score was observed (p-value for interaction term < 0.2), sex-stratified models were used to investigate the sex-dependency of the association of interest. Covariates were selected based on a priori knowledge and impact on the main effect estimate (≥10%). The covariates considered were maternal age, maternal education, pre-pregnancy BMI, marital status, environmental tobacco smoke, alcohol consumption, and number of children. The final models were adjusted for maternal age (continuous), maternal education (categorical; GED or less, some college, Bachelors or higher), child age in months, and child sex (for non-stratified models). Regression results are presented as the percentage difference in score (95% confidence interval) per interquartile range (IQR) increase in urinary phthalate metabolite levels.

3. Results

3.1. Participant Characteristics

Table 1 summarizes the demographic characteristics of mothers and newborns, with characteristics stratified by infant sex and age at assessment in Supplementary Table S1. The present analysis includes 274 participants with prenatal phthalate and childhood outcome measures at the age of 6 months (n = 98), 12 months (n = 130), or 24 months (n = 123) (Figure 1). The distribution of BDI-2 domain/subdomain scores are presented in Figure 2 and Supplementary Table S2. Briefly, the means of BDI-2 total scores were within the normal range (population mean ± 1 SD) for all age points (6 months; 102.8 ± 8.8, 12 months; 94.9 ± 12.3, and 24 months; 103.5 ± 9.7) [36]. More children had communication domain DQ scores 2SD below the population mean (n = 21, 17%) in the 24 months sample compared to the other time points (Supplementary Figure S2). Most measured phthalate metabolites were detected in greater than 80 % of prenatal urine samples as previously reported [37,38]. The distributions of maternal urinary phthalate metabolite levels over the gestation are presented in Supplementary Figure S1 and Supplementary Table S3. The geometric mean of phthalate metabolite levels and distribution in our study population is similar to the previously reported distribution in the larger PROTECT population, with some phthalates higher than NHANES 2011–2016 [30]. We did not observe any significant difference in urinary phthalate metabolite levels between study visits based on a one-way ANOVA test (Supplementary Table S3). Similarly, there was no significant difference in prenatal phthalate metabolite levels between children with assessments at the different age time points (6 months, 12 months, or 24 months) except for DBP (ANOVA, p > 0.05).

3.2. Intrauterine Phthalate Exposure and BDI-2 in Early Childhood

Child neurodevelopment across five domains—adaptive, personal and social, communication, motor, and cognitive—were associated with various phthalate metabolites at different ages (6 months, 12 months, or 24 months), adjusting for maternal age, maternal education, and child age at assessment (Figure 3a: 6 months, Figure 3b: 12 months, Figure 3c: 24 months). For instance, an IQR increase in an in utero urinary MCOP concentration was associated with a 3.28% lower personal-social domain score at 12 months (95% CI: −5.25, −1.3), which indicates poorer performance. Interestingly, MCPP was associated with poorer performance in all five domains of BDI-2 at age 24 months. Specifically, in utero MCPP concentration was associated with 4.95% lower adaptive scores (95% CI: −7.7, −2.2), 4.69% lower cognitive (95% CI: −7.49, −1.9), 10.67% lower communication (95% CI: −15.28, −6.06), 2.45% lower motor (95% CI: −4.35, −0.55), and 5.42% lower personal-social (95% CI: −8.15, −2.69) scores per IQR increase at age 24 months, indicating holistic developmental delay in relation to this urinary metabolite.
We examined interactions between phthalate exposure and sex using cross-product terms and sex-stratified models. Sex-specificity was observed for all time points (p-interaction < 0.2) in all five domains with several phthalate metabolites. Specifically, seven among ten phthalate metabolites—MBZP, MCOP, MCNP, MCPP, MEP, ΣDIBP, ΣDEHP, ΣDEHTP—in the analysis repeatedly showed significant interaction terms throughout different time points. Stratification by infant sex revealed a distinct pattern, where a significant association was often found in one sex but not the other, leading to null associations in the combined analyses.
We found that adaptive and cognitive domains were especially sensitive to the sex-specific effects, generally showing stronger associations among boys compared to girls. For instance, metabolites of a recent phthalate replacement, ΣDEHTP, showed significant associations among boys but not girls for 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 cognitive domain (boys -6.05%/IQR, 95% CI: −10.88, −1.22 vs. girls −1.93%/IQR, 95% CI: −4.14, 0.28) at age 6 months. In addition, at age 12 months, lower adaptive domain scores among boys were associated with MEP and MCOP, while MCOP was also associated with lower cognitive domain scores. Similarly, at age 24 months, we observed an association between ΣDBP and adaptive scores among boys but not girls. Interestingly, MONP and MCOP were associated with lower scores in all five domains at 24 months, with associations again more pronounced among boys.
We observed similar sex-specific associations in other domains as well. At 6 months of age, MEP was associated with communication domain scores (−5.84%/IQR, 95% CI: −10.93, −0.75) among boys, but not girls (0.98%/IQR, 95% CI: −3.82, 5.77). In addition, sex-stratified analysis revealed that for boys, motor scores at age 12 months were negatively associated with MCOP (boys 3.99%/IQR, 95% CI: −7, −0.99 vs. girls 0.59%/IQR, 95% CI: −2.87, 4.06) and at age 24 months with DEHTP (boys 4.95%/IQR, 95% CI: −8.29, −1.61 vs. girls 0.61%/IQR, 95% CI: −2.72, 3.94), but null associations were observed for girls.
In contrast, there are some associations where girls showed stronger relationships. MBZP, specifically, was associated with communication domain scores at 6 months (boys −2.08%/IQR, 95% CI: −6.67, 2.52 vs. girls −3.58%/IQR, 95% CI: −7.07, −0.08) and adaptive scores at age 24 months (boys 0.34%/IQR, 95% CI: −5.48, 6.16 vs. girls −4.3%/IQR, 95% CI: −7.92, −0.68) but associations were only significant among girls. It is also notable that the phthalate replacement, DEHTP, was significantly associated with communication scores at 6 months only among girls (boys 0.45%/IQR, 95% CI: −5.64, 6.53 vs. girls −3.72%/IQR, 95% CI: −6.92, −0.52), while other domain scores at the same age showed stronger associations in boys as described previously. More detailed effect estimates are shown in Supplementary Tables S4a–c.

4. Discussion

In this study, maternal urinary phthalate levels during pregnancy exhibited significant associations with lower BDI scores, a test of child neurodevelopment, at ages 6–24 months across five developmental domains—adaptive, personal-social, communication, motor, and cognitive. Our findings suggest that gestational exposure to phthalates and a recent phthalate replacement could negatively affect early child neurodevelopment with differences by sex. Although associations varied according to developmental age, there were some consistent relationships with specific phthalate metabolites and all five domains. Specifically, MONP and MCOP were associated with lower scores in all five domains at 24 months among boys, indicating holistic delay and sex-specificity. Similarly, MCPP was also negatively associated with all five domains at age 24 months among both sexes. As MCPP is a metabolite of several high-molecular-weight phthalates, these results indicate a possible synergetic or cumulative effect of multiple phthalates on early neurodevelopment.
The prenatal urinary concentrations of phthalate metabolites among PROTECT study participants have been reported and discussed in previous studies [30]. Average BDI domain DQ scores and subdomain scaled scores in the analysis group are within the normal range (within one standard deviation of mean: 100 ± 15 for domain DQ scores and 10 ± 3 for subdomain scaled scores) for all age points, although we observed slightly lower scores of cognitive domain and subdomain at age 24 months compared to other age points (cognitive domain: 86.41 ± 9.99; attention and memory subdomain: 7.42 ± 1.93; perception and concepts subdomain: 7.57 ± 2.12). Cognitive domain and subdomain scores at 6 months and 12 months showed similar distributions.
While studies that used BDI as a neurodevelopmental assessment are limited, previous studies of in utero phthalate exposure and child neurodevelopment reported statistically significant associations between several phthalate metabolites and neurodevelopmental delay in cognitive, motor, and peer relationships in early to mid-childhood [39,40,41,42]. In addition, statistically significant sex-specificity has been reported frequently in previous studies. A study in South Korea found that DEHP metabolites were negatively associated with a mental index of boys at age 6 months [43], and a study of children in Mexico City found that metabolites of DEHP were associated with poorer motor and cognitive scale scores at 48 months of age, with stronger associations observed among boys compared to girls [44]. A study of French mother–son pairs found that MBP was associated with higher internalizing behaviors, relationship problems, and emotional symptoms scores at age 3 years [45]. On the other hand, a few studies suggested stronger associations among girls. Another study of children in Mexico showed third trimester exposure to DEHP was significantly associated with lower mental index scores among girls at 36 months [46], and the Mount Sinai Children’s Environmental Health Study showed that MCPP and MBZP were associated with mental and psychomotor indices at age 24 months specifically in girls [47]. Interestingly, an inconsistency exists for DBP metabolites as significant associations in girls were observed in the Mount Sinai Children’s Environmental Health study [47], while another study from South Korea showed stronger associations among boys at 6 months [43]. In addition, Loftus et al. found no significant associations of gestational exposure to MCOP and MCPP with child language and cognitive ability at age 3 to 6 years. Overall, some inconsistencies exist in previous results, especially in the sex-specific effects of phthalate exposure on child neurodevelopment [48]. The differences may come from differences in the age at neurodevelopmental assessment within each study or differences in phthalate exposure at the population level. Further research is needed pertaining to the role of sex in the relationships between gestational phthalate exposure and child neurodevelopment.
There are a number of potential mechanisms that underlie the associations observed in this study. Phthalates may disrupt the maternal thyroid signaling pathway [49,50,51], which is crucial for early brain development [52]; thus, abnormal maternal thyroid function is associated with child neurodevelopmental delay. Phthalate exposure is also associated with altered sex hormone levels during gestation, which can affect child neurodevelopment by damaging neurotransmitters [6], disrupting development of sex-specific brain structures [53,54], or altering the medial prefrontal cortex function [55,56]. In addition, phthalate exposure may affect child neurodevelopment by causing oxidative stress. Prenatal phthalate exposure has been associated with increased oxidative stress during pregnancy [57], and animal studies have suggested that increased maternal oxidative stress during pregnancy can alter offspring brain development [58,59]. In addition, animal studies have indicated that phthalates can alter the lipid metabolism of the fetal brain [60]. Gestational phthalate exposure has been related to increased lipid peroxidation during pregnancy [57,61], which can lead to motor neuron death and brain disorders [62]. While epidemiological studies of the health effects of phthalate replacements are extremely limited, recent in vitro studies have demonstrated that DEHTP may increase oxidative stress and inflammatory response [63].
A strength of our study is the extensive panel of phthalate and phthalate replacement metabolites, given the limited research on the effects of human exposure to DEHTP. In addition, few if any studies have used the BDI-2 to assess potential changes in neurodevelopment due to gestational phthalate exposure, which enabled us to examine a broad spectrum of child neurodevelopmental outcomes, including adaptive, personal-social, communication, motor, and cognitive domains. Furthermore, we assessed exposures in relation to neurodevelopment early in infancy, which few previous studies have reported. Lastly, our study utilized the PROTECT birth cohort in Puerto Rico, where the population has a high burden of environmental contamination, poverty, and adverse health outcomes, and historically has been medically underserved. Our results will support research translation efforts and inform the development of actionable preventive measures within this vulnerable population.
A major limitation of our study is the small sample size. First, we were not able to evaluate critical windows of susceptibility to exposure across gestation or non-linear relationships, but future work with a larger sample will improve our ability to explore these relationships in more detail. Similarly, we had a relatively small number of individuals with repeated assessments at multiple time points, and we were therefore not able to assess changes over time. Although we observed varying associations between phthalate metabolites and BDI-2 scores at different time points, it is unclear whether this discrepancy came from the inability to detect the relationships at earlier time points due to insufficient sample sizes, or the progression of adverse effects over time. In addition, there were some differences in demographic characteristics between participants with assessments at the different time points, which may at least partially explain our results. However, all models were adjusted for maternal age and education. Therefore, a longitudinal study with a single analysis group to assess the impact of gestational phthalate exposure on neurodevelopmental trajectories is needed. Moreover, our analysis was limited to single pollutants due to the small sample size; however, chemical exposures occur as mixtures and certain phthalates share similar exposure patterns, calling for a need to study cumulative effects. Lastly, even though we observed a trend of stronger associations in boys, the sex-specificity was not conclusive. Thus, further study using advanced mixture methods and elucidating biological mechanisms of sex-dependency will enhance our findings.

5. Conclusions

In conclusion, our results provide evidence supporting the hypothesis that maternal exposure to phthalates or phthalate replacements in pregnancy may have adverse effects on child neurodevelopment across multiple domains during infancy. In addition, our results indicate that these associations may vary by child age and sex. Our findings align with previous studies reporting associations between prenatal phthalate exposure and neurodevelopmental delay in childhood and its dimorphism by sex. This highlights the need for both preventive measures against environmental exposures as well as for accessible, early interventions in developmental delays in Puerto Rico and other marginalized communities. Further research pertaining to the long-term effects of in utero exposure to phthalates on neurodevelopment over early childhood, and elucidating biological underlying mechanisms is essential.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/toxics11010065/s1, Figure S1. Distribution of prenatal phthalate concentration averaged over gestation by age group; Figure S2. Spaghetti plots of the change of BDI domain/subdomain score of children whose score were reported twice (at age around 12 months and 24 months) during the study period. Brown solid lines indicate the change in median score. Table S1. Demographic characteristics of study sample (N = 274); Table S2. Distributions of BDI scores among analysis group (n = 274). Arithmetic means and standard deviation by age group; Table S3. Comparison of uncorrected urinary phthalate and phthalate replacement metabolite concentrations (ng/mL) in study sample (N = 274) by study visit; Table S4. a: Percentage change in BDI-2 scores per IQR increase in the geometric mean of maternal urinary phthalate metabolite concentrations (ng/mL) across pregnancy from 6 months group (n all = 98, n girls = 49, n boys = 49); Table S4. b: Percentage change in BDI-2 scores per IQR increase in the geometric mean of maternal urinary phthalate metabolite concentrations (ng/mL) across pregnancy from 12 months group (n all = 130, n girls = 64, n boys = 66); Table S4. c: Percentage change in BDI-2 scores per IQR increase in the geometric mean of maternal urinary phthalate metabolite concentrations (ng/mL) across pregnancy from 24 months group (n all = 123, n girls = 69, n boys = 54).

Author Contributions

Conceptualization, S.P., J.D.M. and D.J.W.; methodology, S.P., E.Z. and D.J.W.; formal analysis, S.P. and D.J.W.; data curation, G.H.-M. and Z.R.-P.; writing—original draft preparation, S.P.; writing—review and editing, E.Z., G.H.-M., C.M.V.-V., J.F.C., A.A., J.D.M. and D.J.W.; visualization, S.P. and D.J.W.; supervision, D.J.W.; project administration, Z.R.-P., C.M.V.-V. and A.A.; funding acquisition, J.F.C., A.A. and J.D.M. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the Superfund Research Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH; grant number P42ES017198). Additional support was provided from NIEHS grant number P50ES026049, Environmental Protection Agency (EPA; grant number: R836155), and the Environmental influences on Child Health Outcomes (ECHO) program grant number UH3OD023251. ECHO is a nationwide research program supported by the NIH, Office of the Director to enhance child health.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and the research protocol was approved by the Ethics and Research Committees of the University of Puerto Rico (A8570110), the University of Michigan (HUM 00037064), and Northeastern University (10-03-03).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data that were used in this study can be made accessible to researchers upon appropriate request with restrictions to ensure the privacy of human subjects.

Acknowledgments

The authors thank the PROTECT study participants, their families, and nurses and research staff who were engaged and facilitated cohort recruitment and follow-up.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Villagomez, A.N.; Muñoz, F.M.; Peterson, R.L.; Colbert, A.M.; Gladstone, M.; MacDonald, B.; Wilson, R.; Fairlie, L.; Gerner, G.J.; Patterson, J.; et al. Neurodevelopmental delay: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine 2019, 37, 7623–7641. [Google Scholar] [CrossRef] [PubMed]
  2. Zablotsky, B.; Bramlett, M.D.; Visser, S.N.; Danielson, M.L.; Blumberg, S.J. Latent Class Analysis of ADHD Neurodevelopmental and Mental Health Comorbidities. J. Dev. Behav. Pediatr. 2018, 39, 10–19. [Google Scholar] [CrossRef] [PubMed]
  3. Lamsal, R.; Zwicker, J.D. Economic Evaluation of Interventions for Children with Neurodevelopmental Disorders: Opportunities and Challenges. Appl. Health Econ. Health Policy 2017, 15, 763–772. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Ghassabian, A.; Trasande, L. Disruption in Thyroid Signaling Pathway: A Mechanism for the Effect of Endocrine-Disrupting Chemicals on Child Neurodevelopment. Front. Endocrinol. 2018, 9, 204. [Google Scholar] [CrossRef] [PubMed]
  5. Ejaredar, M.; Nyanza, E.C.; Eycke, K.T.; Dewey, D. Phthalate exposure and childrens neurodevelopment: A systematic review. Environ. Res. 2015, 142, 51–60, ISSN 0013-9351. [Google Scholar] [CrossRef] [PubMed]
  6. Xu, S.; Zhang, H.; Pao, P.-C.; Lee, A.; Wang, J.; Chan, Y.S.; Iii, F.A.M.; Chan, S.W.; Cheng, S.H.; Chen, X. Exposure to phthalates impaired neurodevelopment through estrogenic effects and induced DNA damage in neurons. Aquat. Toxicol. 2020, 222, 105469, ISSN 0166-445X. [Google Scholar] [CrossRef]
  7. Lee, S.M.; Jeon, S.; Jeong, H.J.; Kim, B.-N.; Kim, Y. Dibutyl phthalate exposure during gestation and lactation in C57BL/6 mice: Maternal behavior and neurodevelopment in pups. Environ. Res. 2019, 182, 109025. [Google Scholar] [CrossRef]
  8. Harris, C.A.; Henttu, P.; Parker, M.G.; Sumpter, J.P. The estrogenic activity of phthalate esters in vitro. Environ. Health Perspect. 1997, 105, 802–811. [Google Scholar] [CrossRef]
  9. Chen, X.; Xu, S.; Tan, T.; Lee, S.T.; Cheng, S.H.; Lee, F.W.F.; Ho, K.C. Toxicity and estrogenic endocrine dis-rupting activity of phthalates and their mixtures. Int. J. Environ. Res. Public Health 2014, 11, 3156–3168. [Google Scholar] [CrossRef]
  10. Gray, L.E., Jr.; Ostby, J.; Furr, J.; Price, M.; Veeramachaneni, D.R.; Parks, L. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol. Sci. 2000, 58, 350–365. [Google Scholar] [CrossRef]
  11. Christiansen, S.; Boberg, J.; Axelstad, M.; Dalgaard, M.; Vinggaard, A.M.; Metzdorff, S.B.; Hass, U. Low-dose perinatal exposure to di(2-ethylhexyl) phthalate induces anti-androgenic effects in male rats. Reprod. Toxicol. 2010, 30, 313–321. [Google Scholar] [CrossRef] [PubMed]
  12. Sathyanarayana, S.; Barrett, E.; Butts, S.; Wang, C.; Swan, S. Phthalate exposure and reproductive hormone concentrations in pregnancy. Reproduction 2014, 147, 401–409. [Google Scholar] [CrossRef] [PubMed]
  13. Sathyanarayana, S.; Butts, S.; Wang, C.; Barrett, E.; Nguyen, R.; Schwartz, S.M.; Swan, S.H. Early prenatal phthalate exposure, sex steroid hormones, and birth outcomes. J. Clin. Endocrinol. Metab. 2017, 102, 1870–1878. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Pacyga, D.C.; Gardiner, J.C.; Flaws, J.A.; Li, Z.; Calafat, A.M.; Korrick, S.A.; Schantz, S.L.; Strakovsky, R.S. Maternal phthalate and phthalate alternative metabolites and urinary biomarkers of estrogens and testosterones across pregnancy. Environ. Int. 2021, 155, 106676. [Google Scholar] [CrossRef] [PubMed]
  15. Cathey, A.L.; Watkins, D.; Rosario, Z.Y.; Vélez, C.; Alshawabkeh, A.N.; Cordero, J.F.; Meeker, J.D. Associations of Phthalates and Phthalate Replacements with CRH and Other Hormones Among Pregnant Women in Puerto Rico. J. Endocr. Soc. 2019, 3, 1127–1149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Johns, L.E.; Ferguson, K.K.; Soldin, O.P.; Cantonwine, D.E.; Rivera-González, L.O.; Del Toro, L.V.A.; Meeker, J.D. Urinary phthalate metabolites in relation to maternal serum thyroid and sex hormone levels during pregnancy: A longitudinal analysis. Reprod. Biol. Endocrinol. 2015, 13, 4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Day, D.B.; Collett, B.R.; Barrett, E.S.; Bush, N.R.; Swan, S.H.; Wang, C.; TIDES Study Team. Prenatal sex hormones and behavioral outcomes in children. Psychoneuroendocrinology 2020, 113, 104547. [Google Scholar] [CrossRef]
  18. Baud, O.; Berkane, N. Hormonal Changes Associated with Intra-Uterine Growth Restriction: Impact on the Developing Brain and Future Neurodevelopment. Front. Endocrinol. 2019, 10, 179. [Google Scholar] [CrossRef] [Green Version]
  19. Firestein, M.R.; Romeo, R.D.; Winstead, H.; Goldman, D.A.; Grobman, W.A.; Haas, D.; Mercer, B.; Parker, C.; Parry, S.; Reddy, U.; et al. Elevated prenatal maternal sex hormones, but not placental aromatase, are associated with child neurodevelopment. Horm. Behav. 2022, 140, 105125. [Google Scholar] [CrossRef]
  20. Whyatt, R.M.; Liu, X.; Rauh, V.A.; Calafat, A.M.; Just, A.C.; Hoepner, L.; Diaz, D.; Quinn, J.; Adibi, J.; Perera, F.P.; et al. Maternal Prenatal Urinary Phthalate Metabolite Concentrations and Child Mental, Psychomotor, and Behavioral Development at 3 Years of Age. Environ. Health Perspect. 2012, 120, 290–295. [Google Scholar] [CrossRef]
  21. Kobrosly, R.W.; Evans, S.; Miodovnik, A.; Barrett, E.S.; Thurston, S.W.; Calafat, A.M.; Swan, S.H. Prenatal phthalate exposures and neurobehavioral development scores in boys and girls at 6–10 years of age. Environ. Health Perspect. 2014, 122, 521–528. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Kim, S.; Eom, S.; Kim, H.J.; Lee, J.J.; Choi, G.; Choi, S.; Eun, S.H. Association between maternal exposure to major phthalates, heavy metals, and persistent organic pollutants, and the neurodevelopmental performances of their children at 1 to 2 years of age-CHECK cohort study. Sci. Total Environ. 2018, 624, 377–384. [Google Scholar] [CrossRef] [PubMed]
  23. Jankowska, A.; Polańska, K.; Koch, H.M.; Pälmke, C.; Waszkowska, M.; Stańczak, A.; Wesołowska, E.; Hanke, W.; Bose-O’Reilly, S.; Calamandrei, G.; et al. Phthalate exposure and neurodevelopmental outcomes in early school age children from Poland. Environ. Res. 2019, 179, 108829. [Google Scholar] [CrossRef] [PubMed]
  24. Edwards, L.; McCray, N.L.; VanNoy, B.N.; Yau, A.; Geller, R.J.; Adamkiewicz, G.; Zota, A.R. Phthalate and novel plasticizer concentrations in food items from U.S. fast food chains: A preliminary analysis. J. Expo. Sci. Environ. Epidemiol. 2021, 32, 366–373. [Google Scholar] [CrossRef]
  25. Cantonwine, D.E.; Cordero, J.F.; Rivera-González, L.O.; Del Toro, L.V.A.; Ferguson, K.K.; Mukherjee, B.; Calafat, A.M.; Crespo, N.; Jiménez-Vélez, B.; Padilla, I.Y.; et al. Urinary phthalate metabolite concentrations among pregnant women in Northern Puerto Rico: Distribution, temporal variability, and predictors. Environ. Int. 2014, 62, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Meeker, J.D.; Cantonwine, D.E.; Rivera-González, L.O.; Ferguson, K.; Mukherjee, B.; Calafat, A.M.; Ye, X.; Del Toro, L.V.A.; Crespo-Hernández, N.; Jiménez-Vélez, B.; et al. Distribution, Variability, and Predictors of Urinary Concentrations of Phenols and Parabens among Pregnant Women in Puerto Rico. Environ. Sci. Technol. 2013, 47, 3439–3447. [Google Scholar] [CrossRef] [Green Version]
  27. Manjourides, J.; Zimmerman, E.; Watkins, D.J.; Carpenito, T.; Vélez-Vega, C.M.; Huerta-Montañez, G.; Rosario, Z.; Ayala, I.; Vergara, C.; Feric, Z.; et al. Cohort profile: Center for Research on Early Childhood Exposure and Development in Puerto Rico. BMJ Open 2020, 10, e036389. [Google Scholar] [CrossRef]
  28. Meeker, J.D.; Hu, H.; Cantonwine, D.E.; Lamadrid-Figueroa, H.; Calafat, A.M.; Ettinger, A.S.; Hernandez-Avila, M.; Loch-Caruso, R.; Téllez-Rojo, M.M. Urinary phthalate metabolites in relation to preterm birth in Mexico City. Environ. Health Perspect. 2009, 117, 1587–1592. [Google Scholar] [CrossRef] [Green Version]
  29. Silva, M.J.; Samandar, E.; Calafat, A.M.; Ye, X. Identification of di-2-ethylhexyl terephthalate (DEHTP) metabolites using human liver microsomes for biomonitoring applications. Toxicol. Vitr. 2015, 29, 716–721. [Google Scholar] [CrossRef] [Green Version]
  30. Rodríguez-Carmona, Y.; Ashrap, P.; Calafat, A.M.; Ye, X.; Rosario, Z.; Bedrosian, L.D.; Huerta-Montanez, G.; Vélez-Vega, C.M.; Alshawabkeh, A.; Cordero, J.F.; et al. Determinants and characterization of exposure to phthalates, DEHTP and DINCH among pregnant women in the PROTECT birth cohort in Puerto Rico. J. Expo. Sci. Environ. Epidemiol. 2020, 30, 56–69. [Google Scholar] [CrossRef]
  31. Hornung, R.W.; Reed, L.D. Estimation of Average Concentration in the Presence of Nondetectable Values. Appl. Occup. Environ. Hyg. 1990, 5, 46–51. [Google Scholar] [CrossRef]
  32. Zota, A.R.; Calafat, A.M.; Woodruff, T. Temporal Trends in Phthalate Exposures: Findings from the National Health and Nutrition Examination Survey, 2001–2010. Environ. Health Perspect. 2014, 122, 235–241. [Google Scholar] [CrossRef] [Green Version]
  33. Varshavsky, J.R.; Morello-Frosch, R.; Woodruff, T.J.; Zota, A.R. Dietary sources of cumulative phthalates exposure among the U.S. general population in NHANES 2005–2014. Environ. Int. 2018, 115, 417–429. [Google Scholar] [CrossRef] [PubMed]
  34. Woodward, M.J.; Obsekov, V.; Jacobson, M.H.; Kahn, L.G.; Trasande, L. Phthalates and Sex Steroid Hormones Among Men From NHANES, 2013–2016. J. Clin. Endocrinol. Metab. 2020, 105, e1225–e1234. [Google Scholar] [CrossRef] [Green Version]
  35. Bliss, S.L. Test Reviews: Newborg, J. (2005). Battelle Developmental Inventory—Second Edition. Itasca, IL: Riverside. J. Psychoeduc. Assess. 2007, 25, 409–415. [Google Scholar] [CrossRef]
  36. Newborg, J. Battelle Developmental Inventory, 2nd ed.; Riverside: Itasca, IL, USA, 2005. [Google Scholar] [CrossRef]
  37. Ferguson, K.K.; Rosen, E.M.; Rosario, Z.; Feric, Z.; Calafat, A.M.; McElrath, T.F.; Vega, C.V.; Cordero, J.F.; Alshawabkeh, A.; Meeker, J.D. Environmental phthalate exposure and preterm birth in the PROTECT birth cohort. Environ. Int. 2019, 132, 105099. [Google Scholar] [CrossRef]
  38. Zimmerman, E.; Watkins, D.J.; Huerta-Montanez, G.; Pabon, Z.R.; Feric, Z.; Manjourides, J.; Meeker, J.D. Associations of gestational phthalate exposure and non-nutritive suck among infants from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) birth cohort study. Environ. Int. 2021, 152, 106480. [Google Scholar] [CrossRef]
  39. Bellinger, D.C. Prenatal Exposures to Environmental Chemicals and Children’s Neurodevelopment: An Update. Saf. Health Work. 2013, 4, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Radke, E.G.; Braun, J.M.; Nachman, R.M.; Cooper, G.S. Phthalate exposure and neurodevelopment: A systematic review and meta-analysis of human epidemiological evidence. Environ. Int. 2020, 137, 105408. [Google Scholar] [CrossRef]
  41. Zhang, Q.; Chen, X.-Z.; Huang, X.; Wang, M.; Wu, J. The association between prenatal exposure to phthalates and cognition and neurobehavior of children-evidence from birth cohorts. Neurotoxicology 2019, 73, 199–212. [Google Scholar] [CrossRef]
  42. Minatoya, M.; Kishi, R. A review of recent studies on Bisphenol A and phthalate exposures and child neurodevelopment. Int. J. Environ. Res. Public Health 2021, 18, 3585. [Google Scholar] [CrossRef] [PubMed]
  43. Kim, Y.; Ha, E.; Kim, E.; Park, H.; Ha, M.; Kim, J.; Hong, Y.; Chang, N.; Kim, B. Prenatal Exposure to Phthalates and Infant Development at 6 Months: Prospective Mothers and Children’s Environmental Health (MOCEH) Study. Environ. Health Perspect. 2011, 119, 1495–1500. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Torres-Olascoaga, L.; Watkins, D.; Schnaas, L.; Meeker, J.; Solano-Gonzalez, M.; Osorio-Valencia, E.; Peterson, K.; Tellez-Rojo, M.; Tamayo-Ortiz, M. Early Gestational Exposure to High-Molecular-Weight Phthalates and Its Association with 48-Month-Old Children’s Motor and Cognitive Scores. Int. J. Environ. Res. Public Health 2020, 17, 8150. [Google Scholar] [CrossRef]
  45. Philippat, C.; Nakiwala, D.; Calafat, A.M.; Botton, J.; De Agostini, M.; Heude, B.; Slama, R.; The EDEN Mother–Child Study Group. Prenatal Exposure to Nonpersistent Endocrine Disruptors and Behavior in Boys at 3 and 5 Years. Environ. Health Perspect. 2017, 125, 097014. [Google Scholar] [CrossRef] [Green Version]
  46. Téllez-Rojo, M.M.; Cantoral, A.; Cantonwine, D.E.; Schnaas, L.; Peterson, K.; Hu, H.; Meeker, J.D. Prenatal urinary phthalate metabolites levels and neurodevelopment in children at two and three years of age. Sci. Total Environ. 2013, 461–462, 386–390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Doherty, B.T.; Engel, S.M.; Buckley, J.P.; Silva, M.J.; Calafat, A.M.; Wolff, M.S. Prenatal phthalate biomarker concentrations and performance on the Bayley scales of infant development-II in a population of young urban children. Environ. Res. 2017, 152, 51–58. [Google Scholar] [CrossRef] [Green Version]
  48. Loftus, C.T.; Bush, N.R.; Day, D.B.; Ni, Y.; Tylavsky, F.A.; Karr, C.J.; Kannan, K.; Barrett, E.S.; Szpiro, A.A.; Sathyanarayana, S.; et al. Exposure to prenatal phthalate mixtures and neurodevelopment in the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Environ. Int. 2021, 150, 106409. [Google Scholar] [CrossRef]
  49. Donat-Vargas, C.; Perez-Carrascosa, F.; Gomez-Peña, C.; Mustieles, V.; Salcedo-Bellido, I.; Frederiksen, H.; Åkesson, A.; Arrebola, J.P. Associations of serum phthalate metabolites with thyroid hormones in GraMo cohort, Southern Spain. Environ. Pollut. 2021, 287, 117606. [Google Scholar] [CrossRef]
  50. Huang, P.-C.; Kuo, P.-L.; Guo, Y.-L.; Liao, P.-C.; Lee, C.-C. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Hum. Reprod. 2007, 22, 2715–2722. [Google Scholar] [CrossRef]
  51. Yao, H.-Y.; Han, Y.; Gao, H.; Huang, K.; Ge, X.; Xu, Y.-Y.; Xu, Y.-Q.; Jin, Z.-X.; Sheng, J.; Yan, S.-Q.; et al. Maternal phthalate exposure during the first trimester and serum thyroid hormones in pregnant women and their newborns. Chemosphere 2016, 157, 42–48. [Google Scholar] [CrossRef]
  52. Prezioso, G.; Giannini, C.; Chiarelli, F. Effect of Thyroid Hormones on Neurons and Neurodevelopment. Horm. Res. Paediatr. 2018, 90, 73–81. [Google Scholar] [CrossRef] [PubMed]
  53. Morris, J.A.; Jordan, C.L.; Breedlove, S.M. Sexual differentiation of the vertebrate nervous system. Nat. Neurosci. 2004, 7, 1034–1039. [Google Scholar] [CrossRef] [PubMed]
  54. Cohen-Bendahan, C.C.; van de Beek, C.; Berenbaum, S.A. Prenatal sex hormone effects on child and adult sex-typed behavior: Methods and findings. Neurosci. Biobehav. Rev. 2005, 29, 353–384. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Niculae, A.; Pavăl, D. From molecules to behavior: An integrative theory of autism spectrum disorder. Med. Hypotheses 2016, 97, 74–84. [Google Scholar] [CrossRef]
  56. Sellinger, E.P.; Riesgo, V.R.; Brinks, A.S.; Willing, J.; Juraska, J.M. Perinatal phthalate exposure increases devel-opmental apoptosis in the rat medial prefrontal cortex. NeuroToxicology 2021, 87, 167–173. [Google Scholar] [CrossRef] [PubMed]
  57. Ferguson, K.K.; McElrath, T.F.; Chen, Y.H.; Mukherjee, B.; Meeker, J.D. Urinary phthalate metabolites and bi-omarkers of oxidative stress in pregnant women: A repeated measures analysis. Environ. Health Perspect. 2015, 123, 210–216. [Google Scholar] [CrossRef] [Green Version]
  58. Feng, Z.; Zou, X.; Jia, H.; Li, X.; Zhu, Z.; Liu, X.; Bucheli, P.; Ballevre, O.; Hou, Y.; Zhang, W.; et al. Maternal Docosahexaenoic Acid Feeding Protects Against Impairment of Learning and Memory and Oxidative Stress in Prenatally Stressed Rats: Possible Role of Neuronal Mitochondria Metabolism. Antioxid. Redox Signal. 2012, 16, 275–289. [Google Scholar] [CrossRef] [Green Version]
  59. Akhtar, F.; Rouse, C.A.; Catano, G.; Montalvo, M.; Ullevig, S.L.; Asmis, R.; Kharbanda, K.; Maffi, S.K. Acute maternal oxidant exposure causes susceptibility of the fetal brain to inflammation and oxidative stress. J. Neuroinflamm. 2017, 14, 195. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Giuliani, A.; Zuccarini, M.; Cichelli, A.; Khan, H.; Reale, M. Critical Review on the Presence of Phthalates in Food and Evidence of Their Biological Impact. Int. J. Environ. Res. Public Health 2020, 17, 5655. [Google Scholar] [CrossRef]
  61. Holland, N.; Huen, K.; Tran, V.; Street, K.; Nguyen, B.; Bradman, A.; Eskenazi, B. Urinary Phthalate Metabolites and Biomarkers of Oxidative Stress in a Mexican-American Cohort: Variability in Early and Late Pregnancy. Toxics 2016, 4, 7. [Google Scholar] [CrossRef] [Green Version]
  62. Hayashi, M.; Miyata, R.; Tanuma, N. Oxidative Stress in Developmental Brain Disorders. Neurodegener. Dis. 2012, 724, 278–290. [Google Scholar] [CrossRef]
  63. Schaffert, A.; Arnold, J.; Karkossa, I.; Blüher, M.; von Bergen, M.; Schubert, K. The Emerging Plasticizer Alternative DINCH and Its Metabolite MINCH Induce Oxidative Stress and Enhance Inflammatory Responses in Human THP-1 Macrophages. Cells 2021, 10, 2367. [Google Scholar] [CrossRef] [PubMed]
Toxics 11 00065 g001 550
Figure 1. Analysis sample sizes. The present analysis included 274 participants with prenatal phthalate metabolite concentrations and childhood neurobehavioral assessments from at least one timepoint (age 6 months, 12 months, and/or 24 months). The dashed boxes below each analysis sample represent the number of participants with repeated assessment results.
Figure 1. Analysis sample sizes. The present analysis included 274 participants with prenatal phthalate metabolite concentrations and childhood neurobehavioral assessments from at least one timepoint (age 6 months, 12 months, and/or 24 months). The dashed boxes below each analysis sample represent the number of participants with repeated assessment results.
Toxics 11 00065 g001
Toxics 11 00065 g002a 550Toxics 11 00065 g002b 550
Figure 2. Histogram of BDI-2 domain and subdomain scores at 6 months, 12 months, and 24 months. Domain abbreviations: Adaptive (ADP), Personal-Social (PS), Communication (COM), Motor (MOT), and Cognitive (COG).
Figure 2. Histogram of BDI-2 domain and subdomain scores at 6 months, 12 months, and 24 months. Domain abbreviations: Adaptive (ADP), Personal-Social (PS), Communication (COM), Motor (MOT), and Cognitive (COG).
Toxics 11 00065 g002aToxics 11 00065 g002b
Toxics 11 00065 g003a 550Toxics 11 00065 g003b 550Toxics 11 00065 g003c 550Toxics 11 00065 g003d 550Toxics 11 00065 g003e 550Toxics 11 00065 g003f 550
Figure 3. (a). Percentage change in BDI-2 scores at 6 months of age (n = 98) per IQR increase in the geometric mean of maternal urinary phthalate metabolite concentrations (ng/mL) across pregnancy. (b). Percentage change in BDI-2 scores at 12 months of age (n = 98) per IQR increase in the geometric mean of maternal urinary phthalate metabolite concentrations (ng/mL) across pregnancy. (c). Percentage change in BDI-2 scores at 24 months of age (n = 98) per IQR increase in the geometric mean of maternal urinary phthalate metabolite concentrations (ng/mL) across pregnancy.
Figure 3. (a). Percentage change in BDI-2 scores at 6 months of age (n = 98) per IQR increase in the geometric mean of maternal urinary phthalate metabolite concentrations (ng/mL) across pregnancy. (b). Percentage change in BDI-2 scores at 12 months of age (n = 98) per IQR increase in the geometric mean of maternal urinary phthalate metabolite concentrations (ng/mL) across pregnancy. (c). Percentage change in BDI-2 scores at 24 months of age (n = 98) per IQR increase in the geometric mean of maternal urinary phthalate metabolite concentrations (ng/mL) across pregnancy.
Toxics 11 00065 g003aToxics 11 00065 g003bToxics 11 00065 g003cToxics 11 00065 g003dToxics 11 00065 g003eToxics 11 00065 g003f
Table
Table 1. Demographic characteristics of study participants from the Puerto Rico PROTECT cohort (N = 1576) and analysis group (N = 274).
Table 1. Demographic characteristics of study participants from the Puerto Rico PROTECT cohort (N = 1576) and analysis group (N = 274).
PROTECT
(N = 1576)		Analysis Group
(N = 274)
Maternal Characteristicsn (%)n (%)
Alcohol UseNever836 (53)125 (46)
Pre-pregnancy608 (39)123 (45)
Currently EmployedNo573 (36)75 (27)
Yes953 (60)185 (68)
Maternal EducationGED or less337 (21)29 (11)
Some college515 (33)98 (36)
Bachelors or higher674 (43)130 (47)
Annual Income<10 k431 (27)52 (19)
10 k– < 30 k413 (26)84 (31)
30 k– < 50 k300 (19)63 (23)
≥50 k195 (12)34 (12)
Maternal Age (years)18–24583 (37)68 (25)
25–29490 (31)91 (33)
30–34324 (21)58 (21)
35–41173 (11)43 (16)
Marital StatusSingle302 (19)27 (10)
Married805 (51)151 (55)
Cohabitating422 (27)78 (28)
BMI≤25755 (48)128 (47)
>25 to <30427 (27)76 (28)
≥30 289 (18)43 (16)
Number of Children0651 (41)109 (40)
1534 (34)79 (29)
2–5347 (22)72 (26)
Child CharacteristicsMean ± SD or n (%)
Gestational Age (weeks) 38.9 ± 1.939.0 ± 1.7
Birth Weight (grams) 3174 ± 5473162.47 ± 564
SexFemale521 (33)137 (50)
Male566 (36)137 (50)
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Park, S.; Zimmerman, E.; Huerta-Montañez, G.; Rosario-Pabón, Z.; Vélez-Vega, C.M.; Cordero, J.F.; Alshwabekah, A.; Meeker, J.D.; Watkins, D.J. Gestational Exposure to Phthalates and Phthalate Replacements in Relation to Neurodevelopmental Delays in Early Childhood. Toxics 2023, 11, 65. https://doi.org/10.3390/toxics11010065

AMA Style

Park S, Zimmerman E, Huerta-Montañez G, Rosario-Pabón Z, Vélez-Vega CM, Cordero JF, Alshwabekah A, Meeker JD, Watkins DJ. Gestational Exposure to Phthalates and Phthalate Replacements in Relation to Neurodevelopmental Delays in Early Childhood. Toxics. 2023; 11(1):65. https://doi.org/10.3390/toxics11010065

Chicago/Turabian Style

Park, Seonyoung, Emily Zimmerman, Gredia Huerta-Montañez, Zaira Rosario-Pabón, Carmen M. Vélez-Vega, José F. Cordero, Akram Alshwabekah, John D. Meeker, and Deborah J. Watkins. 2023. "Gestational Exposure to Phthalates and Phthalate Replacements in Relation to Neurodevelopmental Delays in Early Childhood" Toxics 11, no. 1: 65. https://doi.org/10.3390/toxics11010065

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop