Reproductive Development And Related Effects Of Phthalate Diesters In Males And Modification By Maternal Stress

Abstract

We propose to expand the concept of endocrine disruption to include non-chemical exposures (psychosocial stress, hyperthermia and malnutrition) that may also interfere with the body's endocrine system and produce adverse health effects. For example, in rodents prenatal stress disrupts the normal surge of testosterone in the developing male and may also act as an androgen on the developing female. Here we present data from two multi-center pregnancy cohort studies in which we examined psychosocial stress in relation to androgen sensitive, sexually dimorphic endpoints. In the first of these studies (The Study for Future Families (SFF); 2000-2002), participants were asked about the occurrence of major stressful life events during pregnancy. We measure anogenital distance (AGD), a sexually dimorphic index of prenatal androgen exposure, in the resulting infants (mean age 16 months). After adjustment for age and body size, females born to couples reporting high stress had significantly longer (i.e. more masculine) AGD than females born to couples reporting low stress (p=0.015). When these children were 4-7 their mothers were asked to complete the Preschool Activities Inventory (PSAI), a standardized questionnaire that measures sexually dimorphic play behavior. We found that girls, but not boys, with a history of more prenatal stressful life events had significantly more masculine scores than those with fewer life events (β=3.48, p=0.006). More recently, in The Infant Development and the Environment Study (TIDES) women were enrolled in four US cities in their first trimester in 2010-2012 and AGD measured in their infants at birth. Phthalate metabolite concentrations were measured in first trimester urine samples and women reported on major stressful life events during pregnancy. We saw a significant inverse association between first trimester exposure to DEHP and AGD in males (sum DEHP metabolites β=-1.26, p=0.029, N=366). While we did not see a direct effect of stress on AGD in this second study, we saw strong evidence that maternal stress modified the phthalate-AGD association. When stratifying by number of stressful life events, this association was stronger in those with low stress (sum DEHP metabolites β=-1.78, p=0.004) but absent in those reporting high stress (β=1.62, p=0.242). Together these preliminary data suggest that prenatal stressful life events may exert androgenic action and modify the effects of prenatal exposure to antiandrogens on genital and neurodevelopment.