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

Abstract

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.

Bisphenols and phthalates: Plastic chemical exposures can contribute to adverse cardiovascular health outcomes

“…Zhang et al, 2020). In pregnant females, the sum of DEHP metabolites can be even higher, ranging from 78.1-93.7 μg/L (Nassan, Gunn, Hill, Williams, & Hauser, 2020;Watkins et al, 2017).…”

Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation

“…EDCs are widespread in the environment and can accumulate throughout the food chain, particularly since most of these lipophilic chemicals exhibit long half-lives [3]. A large body of research has indicated that in humans, prolonged exposure to these chemicals can be associated with metabolic dysfunction, disorders of the reproductive system, endocrine-related cancers, and neurodevelopmental diseases [4][5][6][7][8][9][10][11].…”

“…The impact of BPA on neurodevelopment is not only linked to the effect on the placenta. There is also evidence of a direct effect on the fetus, such as the HPA axis, thyroid receptors, and estrogen receptors [9,[23][24][25]. Moreover, BPA exposure in utero appears to be associated with implantation problems, as well as preeclampsia, preterm births, and low birth weight [26][27][28][29][30].…”

In Utero and Peripubertal Metals Exposure in Relation to Reproductive Hormones and Sexual Maturation and Progression among Boys in Mexico City

“…These trends in the timing of puberty, a period of physical and psychological development, have raised concerns regarding the potential impact of environmental factors, including endocrine disrupting chemicals (EDCs) (Blakemore et al 2010;Buck Louis et al 2008;Lee and Styne 2013;Sisk and Foster 2004). Exposure to EDCs prenatally and at the prepubertal stage are thought to play a role in altered pubertal timing, possibly via their estrogenic or anti-androgenic effects and disruption of normal homeostatic control of the hypothalamic-pituitary-gonadal (HPG) or hypothalamic-pituitary-adrenal (HPA) axis (Bellingham et al 2009;Buck Louis et al 2008;Den Hond and Schoeters 2006;Diamanti-Kandarakis et al 2009;Fudvoye et al 2019; Jacobson-Dickman and Lee 2009;Jansen et al 2018;Massart et al 2006;Parent et al 2016;Pescovitz and Walvoord 2007;Rodriguez et al 2019;Roy et al 2009;Watkins et al 2016;Watkins et al 2017).…”