Stress and Androgen Activity During Fetal Development

Barrett, Emily S.; Swan, Shanna H.

doi:10.1210/en.2015-1335

Cited by 64 publications

(58 citation statements)

References 101 publications

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“…These results are similar with the findings from SFF, our previous, smaller pregnancy cohort, in which associations between prenatal phthalates and AGD were also limited to boys from lower stress families . In SFF, among boys born into ‘lower stress’ households, the strength of the associations between maternal DEHP metabolite concentrations and son's AGD were roughly equivalent to those in the current study (although somewhat stronger for AGD‐AP).…”

Section: Discussionsupporting

confidence: 89%

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

Barrett

Parlett

Sathyanarayana

et al. 2015

Paediatric Perinatal Epid

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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.

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Section: Discussionsupporting

confidence: 89%

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

Barrett

Parlett

Sathyanarayana

et al. 2015

Paediatric Perinatal Epid

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“…There seems to exist a cross talk between fetal glucocorticoids and sex steroid hormones. In fact, prenatal stress, by stimulating HPA axis response which, in turn, upregulates adrenal androgen activity, was also shown to promote a sexually dimorphic response in animal models (Barrett & Swan, ; Hill et al., ; Mueller & Bale, ) These effects, more consistently seen in developing males, include reproductive anomalies (Van den Driesche et al., ), feminization of play behavior, and anxiety‐related behaviors that are concomitant with changes in sexually dimorphic brain nuclei (Arnold & Gorski, ). In humans, investigation shows that prenatal stress is associated with several disorders with sex differences in prevalence such as autism spectrum disorders, schizophrenia, and attention‐deficit/hyperactivity disorder (Khashan et al., ; Kinney, Munir, Crowley, & Miller, ).…”

Section: Other Maternal Hormonal Axis Influence On Fetal Neurodevelopmentioning

confidence: 99%

Maternal hormonal milieu influence on fetal brain development

2018

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An adverse maternal hormonal environment during pregnancy can be associated with abnormal brain growth. Subtle changes in fetal brain development have been observed even for maternal hormone levels within the currently accepted physiologic ranges. In this review, we provide an update of the research data on maternal hormonal impact on fetal neurodevelopment, giving particular emphasis to thyroid hormones and glucocorticoids. Thyroid hormones are required for normal brain development. Despite serum TSH appearing to be the most accurate indicator of thyroid function in pregnancy, maternal serum free T4 levels in the first trimester of pregnancy are the major determinant of postnatal psychomotor development. Even a transient period of maternal hypothyroxinemia at the beginning of neurogenesis can confer a higher risk of expressive language and nonverbal cognitive delays in offspring. Nevertheless, most recent clinical guidelines advocate for targeted high‐risk case finding during first trimester of pregnancy despite universal thyroid function screening. Corticosteroids are determinant in suppressing cell proliferation and stimulating terminal differentiation, a fundamental switch for the maturation of fetal organs. Not surprisingly, intrauterine exposure to stress or high levels of glucocorticoids, endogenous or synthetic, has a molecular and structural impact on brain development and appears to impair cognition and increase anxiety and reactivity to stress. Limbic regions, such as hippocampus and amygdala, are particularly sensitive. Repeated doses of prenatal corticosteroids seem to have short‐term benefits of less respiratory distress and fewer serious health problems in offspring. Nevertheless, neurodevelopmental growth in later childhood and adulthood needs further clarification. Future studies should address the relevance of monitoring the level of thyroid hormones and corticosteroids during pregnancy in the risk stratification for impaired postnatal neurodevelopment.

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“…8 , 9 Hyperandrogenism during pregnancy causes fetal virilization, 10 , 11 intrauterine growth restriction, 12 and low birth weight. 13 These prenatal complications positively correlate with the development in adulthood of hyperinsulinemia 14 , 15 and metabolic disorders such as obesity, 16 , 17 hypertension, 18 and PCOS. 19 , 20 Similar findings of obesity, hyperleptinemia, 21 and hyperinsulinemia (19) have been shown in rats and other animals exposed to excess androgens in utero .…”

Section: Introductionmentioning

confidence: 99%

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

et al. 2018

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Background: Conditions of excess androgen in women, such as polycystic ovary syndrome (PCOS), often exhibit intergenerational transmission. One way in which the risk for PCOS may be increased in daughters of affected women is through exposure to elevated androgens in utero. Hyperandrogenemic conditions have serious health consequences, including increased risk for hypertension and cardiovascular disease. Recently, gut dysbiosis has been found to induce hypertension in rats, such that blood pressure can be normalized through fecal microbial transplant. Therefore, we hypothesized that the hypertension seen in PCOS has early origins in gut dysbiosis caused by in utero exposure to excess androgen. We investigated this hypothesis with a model of prenatal androgen (PNA) exposure and maternal hyperandrogenemia by single-injection of testosterone cypionate or sesame oil vehicle (VEH) to pregnant dams in late gestation. We then completed a gut microbiota and cardiometabolic profile of the adult female offspring. Results: The metabolic assessment revealed that adult PNA rats had increased body weight and increased mRNA expression of adipokines: adipocyte binding protein 2, adiponectin, and leptin in inguinal white adipose tissue. Radiotelemetry analysis revealed hypertension with decreased heart rate in PNA animals. The fecal microbiota profile of PNA animals contained higher relative abundance of bacteria associated with steroid hormone synthesis, Nocardiaceae and Clostridiaceae, and lower abundance of Akkermansia, Bacteroides, Lactobacillus, Clostridium. The PNA animals also had an increased relative abundance of bacteria associated with biosynthesis and elongation of unsaturated short chain fatty acids (SCFAs). Conclusions: We found that prenatal exposure to excess androgen negatively impacted cardiovascular function by increasing systolic and diastolic blood pressure and decreasing heart rate. Prenatal androgen was also associated with gut microbial dysbiosis and altered abundance of bacteria involved in metabolite production of short chain fatty acids. These results suggest that early-life exposure to hyperandrogenemia in daughters of women with PCOS may lead to long-term alterations in gut microbiota and cardiometabolic function.

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Stress and Androgen Activity During Fetal Development

Cited by 64 publications

References 101 publications

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

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

Maternal hormonal milieu influence on fetal brain development

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

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