Association between Maternal Exposure to di(2-ethylhexyl) Phthalate and Reproductive Hormone Levels in Fetal Blood: The Hokkaido Study on Environment and Children's Health

Abstract

Prenatal di(2-ethylhexyl) phthalate (DEHP) exposure can produce reproductive toxicity in animal models. Only limited data exist from human studies on maternal DEHP exposure and its effects on infants. We aimed to examine the associations between DEHP exposure in utero and reproductive hormone levels in cord blood. Between 2002 and 2005, 514 pregnant women agreed to participate in the Hokkaido Study Sapporo Cohort. Maternal blood samples were taken from 23–35 weeks of gestation and the concentration of the primary metabolite of DEHP, mono(2-ethylhexyl) phthalate (MEHP), was measured. Concentrations of infant reproductive hormones including estradiol (E2), total testosterone (T), and progesterone (P4), inhibin B, insulin-like factor 3 (INSL3), steroid hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone were measured from cord blood. Two hundred and two samples with both MEHP and hormones' data were included in statistical analysis. The participants completed a self-administered questionnaire regarding information on maternal characteristics. Gestational age, birth weight and infant sex were obtained from birth records. In an adjusted linear regression analysis fit to all study participants, maternal MEHP levels were found to be associated with reduced levels of T/E2, P4, and inhibin B. For the stratified analyses for sex, inverse associations between maternal MEHP levels T/E2, P4, inhibin B, and INSL3 were statistically significant for males only. In addition, the MEHP quartile model showed a significant p-value trend for P4, inhibin B, and INSL3 decrease in males. Since inhibin B and INSL3 are major secretory products of Sertoli and Leydig cell, respectively, the results of this study suggest that DEHP exposure in utero may have adverse effects on both Sertoli and Leydig cell development in males, which agrees with the results obtained from animal studies. Comprehensive studies investigating phthalates' exposure in humans, as well as their long-term effects on reproductive development are needed.

Impact of phthalate and BPA exposure during in utero windows of susceptibility on reproductive hormones and sexual maturation in peripubertal males

“…However, the second study reported associations between third trimester MEHP levels in maternal blood and reduced testosterone to estradiol ratios and inhibin B among males [10]. In addition, a cross-sectional study of perinatal phthalate exposure reported that MEP and MBP concentrations in breast milk were associated with increased luteinizing hormone to free testosterone ratios and SHBG in male infants at three months of age [28].…”

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

“…Previous studies have shown associations between markers of phthalate and BPA exposure and altered steroid hormone levels in adults (Ehrlich et al 2012; Meeker et al 2009; Mok-Lin et al 2010; Pan et al 2006; Sathyanarayana et al 2014; Sathyanarayana et al 2017), as well as associations between in utero or early life exposure and hormone levels in infants (Araki et al 2014; Lin et al 2011; Main et al 2006). However, few studies have investigated relationships between phthalate or BPA exposure during in utero development and subsequent hormone levels during puberty, a time at which steroid hormones play an essential role in reproductive development.…”

Chronic exposure of adult, postnatal and in utero rat models to low-dose 137Cesium: impact on circulating biomarkers

“…The advantage of measuring markers in the blood to determine the results of exposure to low doses of ionizing radiation has previously been demonstrated experimentally [44, 45]. Accordingly, we evaluated blood biochemistry to identify possible disruptions in general indicators (lipids, proteins, carbohydrates and electrolytes], and biomarkers of thyroid, heart, liver, kidney, brain, bone and testis (steroidogenesis) impairment.…”