Relating Phthalate and BPA Exposure to Metabolism in Peripubescence: The Role of Exposure Timing, Sex, and Puberty

Watkins, Deborah J.; Peterson, Karen E.; Ferguson, Kelly K.; Mercado‐García, Adriana; Ortiz, Marcela Tamayo y; Cantoral, Alejandra; Meeker, John D.; Téllez-Rojo, Martha M.

doi:10.1210/jc.2015-2706

Cited by 66 publications

(64 citation statements)

References 36 publications

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“…Associations of in utero phthalate and BPA exposure with pubertal timing could be mediated through disruption of metabolic homeostasis, as previous studies have demonstrated associations between exposure and altered peripubertal leptin levels (Volberg et al 2013; Watkins et al 2016). Higher levels of leptin are necessary for the onset of puberty, as this signals that energy stores are adequate for reproductive development and maturity (Bordini and Rosenfield 2011).…”

Section: Discussionmentioning

confidence: 97%

Phthalate and bisphenol A exposure during in utero windows of susceptibility in relation to reproductive hormones and pubertal development in girls

Watkins

Sánchez

Téllez-Rojo

et al. 2017

Environmental Research

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105

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Background Over the past several decades, the age of pubertal onset in girls has shifted downward worldwide. As early pubertal onset is associated with increased risky behavior and psychological issues during adolescence and cardiometabolic disease and cancer in adulthood, this is an important public health concern. Exposure to endocrine disrupting chemicals during critical windows of in utero development may play a role in this trend. Our objective was to investigate trimester-specific phthalate and BPA exposure in relation to pubertal development among girls in the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohort. Methods We measured maternal urinary phthalate metabolites and BPA in samples collected during the first, second, and third trimesters of pregnancy. To assess reproductive development among their female children, we measured serum testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), inhibin B, and sex hormone-binding globulin (SHBG), and assessed sexual maturation, including Tanner staging for breast and pubic hair development and menarche status, at age 8–13 years (n=120). We used linear and logistic regression to examine measures of trimester-specific in utero exposure as predictors of peripubertal hormone levels and pubertal onset, respectively. In secondary analyses, we evaluated estimated exposure at the midpoint of the first trimester and rates of change in exposure across pregnancy in relation to outcomes. Results Several phthalate metabolites measured throughout in utero development were associated with higher serum testosterone concentrations, while a number of metabolites measured in the third trimester were associated with higher DHEA-S. For example, an interquartile range (IQR) increase in mean monoethyl phthalate (MEP) levels across pregnancy was associated with 44% higher peripubertal testosterone (95% CI: 13–83%), while an IQR increase in di-2-ethylhexyl phthalate metabolites (ΣDEHP) specifically in the third trimester was associated with 25% higher DHEA-S (95%CI: 4.7–47%). In IQR increase in mean mono-2-ethylhexyl phthalate (MEHP) levels across pregnancy was associated with lower odds of having a Tanner Stage >1 for breast development (OR=0.32, 95%CI: 0.11–0.95), while MEHP in the third trimester was associated with higher odds of having a Tanner Stage >1 for pubic hair development (OR=3.76, 95%CI: 1.1–12.8). Results from secondary analyses were consistent with findings from our main analysis. Conclusion These findings suggest that female reproductive development may be more vulnerable to the effects of phthalate or BPA exposure during specific critical periods of in utero development. This highlights the need for comprehensive characterizations of in utero exposure and consideration of windows of susceptibility in developmental epidemiological studies. Future research should consider repeated measures of in utero phthalate and BPA exposure within each trimester and across pregnancy.

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Section: Discussionmentioning

confidence: 97%

Phthalate and bisphenol A exposure during in utero windows of susceptibility in relation to reproductive hormones and pubertal development in girls

Watkins

Sánchez

Téllez-Rojo

et al. 2017

Environmental Research

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105

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“…A pediatrician assessed each child to determine Tanner stage for genital (boys), breast (girls), and pubic hair (both) development. For this analysis, we dichotomized pubertal status as prepubertal vs. pubertal: boys were considered pubertal if they received an assessment of Tanner stage >1 for genital or pubic hair development, and girls were considered pubertal if they received an assessment of Tanner stage >1 for breast or pubic hair development (24). …”

Section: Methodsmentioning

confidence: 99%

“…These compounds are of particular interest to the ELEMENT cohort due to their known endocrine-disrupting activities and established association with other metabolic risk factors this population (24, 26). To assess overall in utero exposure, we calculated geometric mean (GM) BPA and phthalate metabolite concentrations for each individual using measurements from each trimester as we have found that this approach provides a more robust measure of exposure for short-lived toxicants, like BPA and phthalates (27, 28).…”

Section: Methodsmentioning

confidence: 99%

“…Likewise, we created a summary score for dibutyl phthalate metabolites (ΣDBP) as the molar sum of MnBP and MiBP. As we have previously done (24), we used these scores in the analysis rather than their component metabolites to reduce the possibility of false positive associations. Values below the limit of detection (LOD) were calculated as LOD/√2.…”

Section: Methodsmentioning

confidence: 99%

“…Next, to evaluate for non-linear associations, we examined associations of quartiles of urinary concentrations of maternal and peripubertal urinary BPA and phthalate metabolites with each lipid using linear regression. Since associations were monotonic across quartiles, we assessed phthalates and BPA continuously to maximize power, and present results as a % difference in each lipid per interquartile range (IQR) increment in the EDC of interest as we have done in prior publications (24). In multivariable analyses, we adjusted for urinary specific gravity and child’s sex and age, followed by further adjustment for pubertal status.…”

Section: Methodsmentioning

confidence: 99%

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Exposure to phthalates is associated with lipid profile in peripubertal Mexican youth

Perng

Watkins

Cantoral³

et al. 2017

Environmental Research

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Animal models indicate that endocrine disrupting chemicals (EDCs) affect circulating lipid concentrations by interfering with hepatic fatty acid oxidation. Little is known of the relationship between EDC exposure and lipid profile in humans. We measured bisphenol A (BPA) and 9 phthalate metabolites in maternal urine collected at up to three time points during pregnancy as a measure of in utero exposure, and in the child’s urine at 8–14 years as a measure of concurrent, peripubertal exposure among 248 participants of a Mexico City pre-birth cohort. We used linear regression to examine relations of BPA and phthalate exposure with peripubertal serum lipids, while also adjusting for child age, sex, and specific gravity. While in utero EDC exposure was not associated with lipid profile, higher concurrent levels of mono-3-carboxypropyl phthalate (MCPP), monoethyl phthalate (MEP), and dibutyl phthalate metabolites (DBP) corresponded with lower total cholesterol and low-density lipoprotein (LDL-C) in boys; e.g., an interquartile range increment in MCPP corresponded with 7.4% (2.0%, 12.8%) lower total cholesterol and 12.7% (3.8%, 21.6%) lower LDL-C. In girls, higher urinary di-2-ethylhexyl phthalate metabolites (ΣDEHP) correlated with lower LDL-C (−7.9% [−15.4%, −0.4%]). Additional longitudinal research is needed to determine whether these associations persist beyond adolescence.

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Mechanistic screening of reproductive toxicity in a novel 3D testicular co-culture model shows significant impairments following exposure to low-dibutyl phthalate concentrations

Almamoun,

Pierozan,

Karlsson

2024

Arch Toxicol

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To improve the mechanistic screening of reproductive toxicants in chemical-risk assessment and drug development, we have developed a three-dimensional (3D) heterogenous testicular co-culture model from neonatal mice. Di-n-butyl phthalate (DBP), an environmental contaminant that can affect reproductive health negatively, was used as a model compound to illustrate the utility of the in vitro model. The cells were treated with DBP (1 nM to 100 µM) for 7 days. Automated high-content imaging confirmed the presence of cell-specific markers of Leydig cells (CYP11A1 +), Sertoli cells (SOX9 +), and germ cells (DAZL +). Steroidogenic activity of Leydig cells was demonstrated by analyzing testosterone levels in the culture medium. DBP induced a concentration-dependent reduction in testosterone levels and decreased the number of Leydig cells compared to vehicle control. The levels of steroidogenic regulator StAR and the steroidogenic enzyme CYP11A1 were decreased already at the lowest DBP concentration (1 nM), demonstrating upstream effects in the testosterone biosynthesis pathway. Furthermore, exposure to 10 nM DBP decreased the levels of the germ cell-specific RNA binding protein DAZL, central for the spermatogenesis. The 3D model also captured the development of the Sertoli cell junction proteins, N-cadherin and Zonula occludens protein 1 (ZO-1), critical for the blood–testis barrier. However, DBP exposure did not significantly alter the cadherin and ZO-1 levels. Altogether, this 3D in vitro system models testicular cellular signaling and function, making it a powerful tool for mechanistic screening of developmental testicular toxicity. This can open a new avenue for high throughput screening of chemically-induced reproductive toxicity during sensitive developmental phases.

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Relating Phthalate and BPA Exposure to Metabolism in Peripubescence: The Role of Exposure Timing, Sex, and Puberty

Abstract: Considering the long-term health effects related to metabolic syndrome, additional research on exposure and metabolic outcomes across developmental periods and early adulthood is needed.

Cited by 66 publications

References 36 publications

Phthalate and bisphenol A exposure during in utero windows of susceptibility in relation to reproductive hormones and pubertal development in girls

Phthalate and bisphenol A exposure during in utero windows of susceptibility in relation to reproductive hormones and pubertal development in girls

Exposure to phthalates is associated with lipid profile in peripubertal Mexican youth

Mechanistic screening of reproductive toxicity in a novel 3D testicular co-culture model shows significant impairments following exposure to low-dibutyl phthalate concentrations

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