Could chemicals found in everyday plastics, furniture and electronics leave a lasting imprint on children's bones? Researchers uncover subtle links between prenatal chemical exposure and slower bone mineral accumulation during adolescence, particularly in males, while most associations remain inconclusive.
Study: Gestational Exposure to Organophosphate Esters and Bone Health at Age 18 Years: The Health Outcomes and Measures of the Environment (HOME) Study. Image credit: Halfpoint/Shutterstock.com
A recent paper in the journal Environment & Health explores the state of bone health at 18 years in offspring of women exposed to organophosphate esters during pregnancy.
Prenatal chemical exposure and lifelong bone health
Peak bone mass is generally attained by the end of adolescence or early adulthood, depending on the skeletal site. Suboptimal accrual during this period is associated with low bone mineral density (BMD), which may increase the risk of osteoporosis and fractures later in life. Osteoporosis is a major contributor to reduced quality of life, short-term disability, and economic losses from reduced productivity and informal or formal caregiving, among other factors.
Organophosphate esters (OPEs) are plasticizers, flame retardants, and lubricants found in plastics, textiles, paints, electronics, furniture, and personal care products. They are widespread in household dust, and the NHANES survey detects several of their urinary metabolites in most US adolescents. OPEs are endocrine-disrupting chemicals. Certain OPEs can activate PPAR-γ, alter sex steroid and thyroid signaling, and in rodent studies, exposure to the flame-retardant mixture Firemaster 550 lowered bone density and disrupted skeletal development.
However, little is known about this topic in humans. The authors’ earlier analysis of this cohort, examining bone density at age 12, was the only prospective human study on the topic. No prospective study had examined offspring of women with gestational OPE exposure for their bone outcomes in late adolescence or after peak bone mass was reached. Moreover, none used 3D bone imaging to assess geometry and strength alongside density. The current paper sought to fill this research gap.
Measuring chemical exposure and bone development across adolescence
This study used data from the HOME Study, which is a pregnancy and birth cohort in the Cincinnati area. Researchers recruited women between 2003 and 2006, particularly those living in homes built before 1978.
Of the mothers, 43% were nulliparous, 65% identified as non-Hispanic White, and 39% had a baseline household income between $40,000 and $80,000. The average maternal midpregnancy body mass index (BMI) and age at delivery were 27.5 kg/m2 and 30.1 years, respectively.
For the main analysis, the authors investigated bone health at 18 years in 218 adolescents born to 216 mothers. This included 99 males and 119 females. A longitudinal assessment of bone accrual patterns was performed in a subset of 175 adolescents who had DXA scans at both 12 and 18 years.
The authors used spot urine samples at about 16 and 26 weeks of gestation to measure OPE exposure. Four OPE metabolites were measured at the CDC: BDCIPP, BCEP, diphenyl phosphate (DPHP) and DnBP. Each metabolite was modeled as a log2-transformed continuous variable (using the geometric mean of available urine dilution-adjusted measurements over the two pregnancy visits), with results expressed per interquartile range (IQR) increase.
At age 18, the authors assessed bone health using the following measures:
- Peripheral quantitative computed tomography (pQCT) to measure radial trabecular and cortical volumetric BMD, cortical thickness, and the strength-strain index (SSI).
- Dual-energy X-ray absorptiometry (DXA) to measure areal BMD (aBMD) at six sites (whole body less head, total hip, femoral neck, 1/3 distal radius, ultradistal radius, lumbar spine), expressed as age- and sex-standardized, race-neutral Z-scores, adjusted for height where appropriate. Lumbar spine used bone mineral apparent density (BMAD), a size-corrected density measure.
- Annualized percent BMD accrual between ages 12 and 18.
The authors modeled all associations using linear regressions fitted with generalized estimating equations. The analyses were adjusted for household income, maternal prepregnancy BMI, maternal age, maternal race/ethnicity, and maternal serum cotinine, as well as adolescent age and sex where required.
Sex-specific differences were tested by stratification, though the statistical significance threshold was less conservative because of limited power. Sensitivity analyses incorporated diet quality and dietary calcium and vitamin D intake, obtaining similar results.
Prenatal chemical exposure shows limited links to bone health
Overall, the authors did not find strong associations between bone health at age 18 and gestational OPE exposure. The authors note that most associations were null and imprecise. The signals were site-specific and sex-specific, with modest effect sizes.
With pQCT, they found weak inverse associations between BCEP and DPHP, and trabecular and cortical volumetric BMD (vBMD). For example, an IQR increase in BCEP corresponded to a 3.18 mg/cm3 decrease in trabecular vBMD, and DPHP to a decrease of 2.64 mg/cm3. However, none were statistically significant.
There were no statistically significant associations with SSI. Similarly, cortical thickness showed no statistically significant overall association.
Males show subtle differences in bone density and thickness
Among males, each IQR increase in DPHP was linked to a reduction in cortical thickness by 0.09 mm, though the confidence interval included zero. An IQR increase in BCEP was linked to a 7.74 mg/cm3 lower trabecular vBMD, although this association was also not statistically significant.
No statistically significant associations were found among females, and there were no significant sex differences in the pQCT measurements on comparison of the stratified estimates (all p > 0.10).
Bone mineral density associations vary by chemical
Before adjustment, all four biomarkers were positively associated with BMD Z-scores, but this largely disappeared in the adjusted models. BDCIPP showed a trend toward a positive association, for example, a 0.22 higher spine BMD Z-score per IQR increase.
Conversely, DPHP trended negative, with lower Z-scores at whole body, less head, total hip, and spine.
Bone density associations differ between male and female adolescents
For BCEP, the spine BMAD Z-score was 0.38 lower per IQR increase among males, but no significant association was found among females. Evidence of sex differences was observed at both the spine and ultradistal radius. DPHP in males was also linked to lower whole-body, less-head, and spine aBMD Z-scores, with null results in females, although these associations were not statistically significant.
Prenatal chemical exposure linked to slower adolescent bone accrual
Bone mineral density generally increased during adolescence, but higher concentrations of certain OPE biomarkers were associated with slower bone mineral accumulation. BDCIPP and BCEP were associated with lower annual accrual at the 1/3 distal radius, by 0.26 and 0.23 percentage points, respectively. DPHP and DnBP were associated with lower accrual at the ultradistal radius by approximately 0.36 to 0.37 points, though those intervals just crossed zero.
Among males, each IQR increase in DPHP was associated with annualized whole-body (excluding the head) accrual and spine accrual rates that were 0.43 and 0.39 percentage points lower, respectively, with significant sex differences at the less conservative significance threshold. In females, DPHP trends were opposite in direction, with higher accrual at the spine (0.46 percentage points), although not statistically significant.
In males, DPHP was also linked to significantly lower annualized accrual at the total hip (0.52 percentage points) and femoral neck (0.49 percentage points), although sex differences at these sites were not statistically significant.
Puberty may shape chemical associations with bone development
Higher gestational DPHP concentrations were associated with reduced cortical bone thickness, lower areal BMD, and slower annualized bone accrual. These associations were observed mainly in males. However, while associations with cortical thickness and BMD Z-scores were imprecise, several associations with reduced bone accrual among males were statistically significant.
The authors note that sex patterns differed from the age-12 analysis, where DPHP was linked to lower BMD in females. Since more girls than boys in the cohort had begun puberty by 12 years, the authors suggest that the effect of gestational DPHP exposure may become observable after the onset of puberty.
BCEP showed a consistent male-specific inverse association with spine BMAD at both ages 12 and 18. However, conflicting findings occurred with BDCIPP, which tended to be associated with higher BMD Z-scores at 12 and 18, especially at the spine, but also with reduced radius accrual. At the radius, slower accrual meant that the higher BMD observed at age 12 was no longer apparent at age 18.
The pQCT results failed to show similar evidence of benefit. The authors argue that the sole use of DXA to assess BMD does not fully capture bone geometry or strength, which are also important parameters for bone health. For example, they cite fluoride, which is linked to a higher areal BMD but also a higher fracture risk. Therefore, they warn against interpreting the positive associations with BDCIPP as evidence of benefit.
The authors suggest that trabecular bone may be particularly susceptible to gestational OPE exposure, as this is the spongy and metabolically active compartment. This possibility is supported by associations involving DPHP at the ultradistal radius and spine. This agrees with rat data where FM 550 exposure reduced trabecular thickness in males, but gestational and lactational OPE exposure increased bone volume fraction in females.
Previous research links chemical exposure to lower bone density
A cross-sectional NHANES study in children and adolescents found inverse associations between BDCIPP, BCEP, and DPHP and aBMD, with stronger inverse associations involving DnBP in males. An adult NHANES study found similar negative associations between the OPE biomarker combination and spine aBMD in men.
However, these were cross-sectional and did not capture gestational exposure data.
How everyday chemicals could interfere with bone formation
The authors propose several mechanisms for the inverse associations with bone density. Certain OPEs may promote PPAR-γ activation, which may encourage bone marrow stem cells to differentiate into fat cells rather than bone-forming osteoblasts.
Another possibility is OPE-associated disruption of estrogen and testosterone signaling, which could explain the stronger associations observed among males. Alterations in thyroid hormone function could also influence bone density changes.
Strengths and limitations
The study’s strengths include a prospective longitudinal design with good retention, complementary imaging platforms to capture bone geometry and strength, the use of the same DXA scanner at both visits, exposure averaged over two time points to reduce misclassification given the short half-lives of OPEs, and sex-specific analyses.
The authors acknowledge several limitations. Only four metabolites were assessed, and no mixture was analyzed. The sex-stratified analyses had limited power due to small samples, and did not include formal exposure-by-sex interaction testing. These findings should, therefore, be interpreted cautiously.
The pQCT scanner was not high-resolution, which may have reduced measurement precision in some cases. The analysis did not account for differences in physical activity and hormonal variations in adolescence. However, these arise after exposure and so are unlikely to confound, and the Z-scores help account for variation in BMD related to age, sexual maturation, and bone size.
Long-term implications for osteoporosis and fracture risk remain unclear
Gestational OPE exposure showed mixed, predominantly null associations with bone health at 18. The clearest pattern was an association between higher DPHP concentrations and lower cortical thickness, lower BMD, and slower accrual, particularly in males.
BDCIPP tended to be linked to higher BMD but reduced radius accrual, and the pQCT data do not support a beneficial effect on bone health. The authors call for replication in larger, more diverse cohorts, with greater focus on changes in trabecular bone, and whether these small differences are clinically relevant to fracture risk and osteoporosis.
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