Prenatal Stress as a Modifier of Associations between Phthalate Exposure and Reproductive Development: results from a Multicentre Pregnancy Cohort Study

Abstract

Background Prenatal phthalate exposure is associated with altered male reproductive tract development, and in particular, shorter anogenital distance (AGD). AGD, a sexually dimorphic index of prenatal androgen exposure, may also be altered by prenatal stress. How these exposures interact to impact AGD is unknown. Here we examine the extent to which associations between prenatal phthalate exposure and infant AGD are modified by prenatal exposure to stressful life events (SLEs). Methods Phthalate metabolites (including those of diethylhexyl phthalate [DEHP] and their molar sum [∑DEHP]) were measured in first trimester urine from 738 pregnant women participating in The Infant Development and the Environment Study (TIDES). Women completed questionnaires on SLEs, and permitted infant AGD measurements at birth. Subjects were classified as “lower” and “higher” stress (0 first trimester SLEs vs. 1+).We estimated relationships between phthalate concentrations and AGD (by infant sex and stress group) using adjusted multiple regression interaction models. Results In the lower stress group, first trimester ∑DEHP was inversely associated with two measures of male AGD: anoscrotal distance (AGD-AS; β=−1.78; 95% CI: −2.97, −0.59) and anopenile distance (AGD-AP; β=−1.61; 95% CI: −3.01, −0.22). By contrast, associations in the higher stress group were mostly positive and non-significant in male infants. No associations were observed in girls. Conclusions Associations between prenatal phthalate exposure and altered genital development were only apparent in sons of mothers who reported no SLEs during pregnancy. Prenatal stress and phthalates may interact to shape fetal development in ways that have not been previously explored.

Sex-Specific Effects of Combined Exposure to Chemical and Non-chemical Stressors on Neuroendocrine Development: a Review of Recent Findings and Putative Mechanisms

“…Stress was measured using a scale of stressful life events administered to couples during pregnancy and DEHP metabolites were measured in a maternal spot urine sample. Consistent with previous findings [44], stressful life events and DEHP exposure were independently associated with reduced anogenital distance among boys, albeit the association with stressful life events was not statistically significant [43]. Interestingly, when stratified by stress (<4 vs. 4+ stressful life events), DEHP metabolites were associated with reduced anogenital distance only among boys in the low stress group.…”

The environmental injustice of beauty: framing chemical exposures from beauty products as a health disparities concern

“…77 Researchers are trying to integrate beauty products into the exposome by characterizing the biologic activity of beauty products using in vitro study designs 56 as well as estimating the joint effects of chemicals and psychosocial stress on reproductive endpoints. 78 Future research should also consider the heterogeneous social and economic factors that drive product use. Collectively, this multi-pronged approach can help advance the ACOG and FIGO recommendations to secure environmental justice and advance health equity.…”

Increased Urinary Phthalate Levels in Women with Uterine Leiomyoma: A Case-Control Study

“…The relatively long half-lives for elimination make 5cx-MEHP and 2cx-MMHP excellent parameters for measuring the time-weighted body burden of DEHP. In studies examining estrogen-dependent diseases, MEHHP and MEOHP are primarily analyzed [22]; therefore, analysis of 5cx-MEHP and 2cx-MMHP, as well as the molar sum of these metabolites (e.g., ∑4-DEHP, ∑5-DEHP, and ∑2-DEHP) is a relatively new strategy [32,33,34,35]. …”

“…Therefore, to determine total exposure to DEHP, we calculated the urinary level of these metabolites by summing the molar concentrations of MEHP, MEHHP, and MEOHP (∑3-DEHP) as previously described (∑3-DEHP = (MEHP × (1/278.34)) + (MEHHP × (1/294.34)) + (MEOHP × (1/292.33)) nmol/mL) [31,32]. We also calculated the molar sum of 4-DEHP and 5-DEHP by combining the levels of ∑3-DEHP plus 5cx-MEPP (∑4-DEHP = ∑3-DEHP + (5cx-MEPP × (1/308.33)) nmol/mL), and 2cx-MMHP (∑5-DEHP = ∑4-DEHP + (2cx-MMHP × (1/308.33)) nmol/mL), respectively [33,34,35].…”