Relationships between lead biomarkers and diurnal salivary cortisol indices in pregnant women from Mexico City: a cross-sectional study

Background: Lead (Pb) exposure during pregnancy may increase the risk of adverse maternal, infant, or childhood health outcomes by interfering with hypothalamic-pituitary-adrenal-axis function. We examined relationships between maternal blood or bone Pb concentrations and features of diurnal cortisol profiles in 936 pregnant women from Mexico City. Methods: From 2007–11 we recruited women from hospitals/clinics affiliated with the Mexican Social Security System. Pb was measured in blood (BPb) during the second trimester and in mothers’ tibia and patella 1-month postpartum. We characterized maternal HPA-axis function using 10 timed salivary cortisol measurements collected over 2-days (mean: 19.7, range: 14–35 weeks gestation). We used linear mixed models to examine the relationship between Pb biomarkers and cortisol area under the curve (AUC), awakening response (CAR), and diurnal slope. Results: After adjustment for confounders, women in the highest quintile of BPb concentrations had a reduced CAR (Ratio: −13%; Confidence Interval [CI]: −24, 1, p-value for trend < 0.05) compared to women in the lowest quintile. Tibia/patella Pb concentrations were not associated with CAR, but diurnal cortisol slopes were suggestively flatter among women in the highest patella Pb quantile compared to women in the lowest quantile (Ratio: 14%; CI: −2, 33). BPb and bone Pb concentrations were not associated with cortisol AUC. Conclusions: Concurrent blood Pb levels were associated with cortisol awakening response in these pregnant women and this might explain adverse health outcomes associated with Pb. Further research is needed to confirm these results and determine if other environmental chemicals disrupt hypothalamic-pituitary-adrenal-axis function during pregnancy

Longitudinal associations of age and prenatal lead exposure on cortisol secretion of 12–24 month-old infants from Mexico City

Background: Cortisol has functions on homeostasis, growth, neurodevelopment, immune function and the stress response. Secretion follows a diurnal rhythm that mediates these processes. Our objective was to examine the association between prenatal lead exposure and infant diurnal cortisol rhythms. Methods: We measured infant cortisol rhythms in saliva collected repeatedly over 2 days at either 12 (n = 255) or 18–24 (n = 150) months of age. Prenatal lead exposure was assessed by measuring maternal pregnancy blood lead levels and early postnatal maternal bone lead content. We analyzed age-specific basal secretion and the association between trimester-specific and cumulative lead exposure with a) change in total diurnal cortisol and b) the shape of the cortisol curve across the length of the day. Results: Our results showed age related differences in salivary cortisol secretion and an age dependent association with maternal lead exposure. In age-stratified models we saw an inverse association between lead and cortisol levels in 12-month-old infants and a positive association for 18–24-month-old infants. For the 12-month-old infants 2nd-trimester-lead ≥10 μg/dL was associated with 40 % lower cortisol levels (95 % CI (−57, −16)) and a significant change in the shape of the cortisol curve (p = 0.01), compared to infants with low blood lead levels (<5 μg/dL). Conclusions: Basal cortisol secretion changes with age. Increased early gestation lead exposure alters diurnal cortisol rhythms and the association is modified by infant age, perhaps representing an early maturation of cortisol homeostasis. Electronic supplementary material The online version of this article (doi:10.1186/s12940-016-0124-1) contains supplementary material, which is available to authorized users

Relationships between lead biomarkers and diurnal salivary cortisol indices in pregnant women from Mexico City: a cross-sectional study

Abstract Background Lead (Pb) exposure during pregnancy may increase the risk of adverse maternal, infant, or childhood health outcomes by interfering with hypothalamic-pituitary-adrenal-axis function. We examined relationships between maternal blood or bone Pb concentrations and features of diurnal cortisol profiles in 936 pregnant women from Mexico City. Methods From 2007–11 we recruited women from hospitals/clinics affiliated with the Mexican Social Security System. Pb was measured in blood (BPb) during the second trimester and in mothers’ tibia and patella 1-month postpartum. We characterized maternal HPA-axis function using 10 timed salivary cortisol measurements collected over 2-days (mean: 19.7, range: 14–35 weeks gestation). We used linear mixed models to examine the relationship between Pb biomarkers and cortisol area under the curve (AUC), awakening response (CAR), and diurnal slope. Results After adjustment for confounders, women in the highest quintile of BPb concentrations had a reduced CAR (Ratio: −13%; Confidence Interval [CI]: −24, 1, p-value for trend < 0.05) compared to women in the lowest quintile. Tibia/patella Pb concentrations were not associated with CAR, but diurnal cortisol slopes were suggestively flatter among women in the highest patella Pb quantile compared to women in the lowest quantile (Ratio: 14%; CI: −2, 33). BPb and bone Pb concentrations were not associated with cortisol AUC. Conclusions Concurrent blood Pb levels were associated with cortisol awakening response in these pregnant women and this might explain adverse health outcomes associated with Pb. Further research is needed to confirm these results and determine if other environmental chemicals disrupt hypothalamic-pituitary-adrenal-axis function during pregnancy

Mercury and psychosocial stress exposure interact to predict maternal diurnal cortisol during pregnancy

Background: Disrupted maternal prenatal cortisol production influences offspring development. Factors influencing the hypothalamic-pituitary-adrenal axis include social (e.g., stressful life events) and physical/chemical (e.g., toxic metals) pollutants. Mercury (Hg) is a common contaminant of fish and exposure is widespread in the US. No prior study has examined the joint associations of stress and mercury with maternal cortisol profiles in pregnancy. Objectives: To investigate potential synergistic influences of prenatal stress and Hg exposures on diurnal cortisol in pregnant women. Methods: Analyses included 732 women (aged 27.4 ± 5.6 years) from a Mexico City pregnancy cohort. Participants collected saliva samples on two consecutive days (mean 19.52 ± 3.00 weeks gestation) and reported life stressors over the past 6 months. Hg was assessed in toe nail clippings collected during pregnancy. Results: There were no main effects of Hg or psychosocial stress exposure on diurnal cortisol (ps > .20) but strong evidence of interaction effects on cortisol slope (interaction B = .006, SE = .003, p = .034) and cortisol at times 1 and 2 (interaction B = -.071, SE = .028, p = .013; B = -.078, SE = .032, p = .014). Women above the median for Hg and psychosocial stress exposure experienced a blunted morning cortisol response compared to women exposed to higher stress but lower Hg levels. Conclusions: Social and physical environmental factors interact to alter aspects of maternal diurnal cortisol during pregnancy. Research focusing solely on either domain may miss synergistic influences with potentially important consequences to the offspring

Offspring DNA methylation of the aryl-hydrocarbon receptor repressor gene is associated with maternal BMI, gestational age, and birth weight

<div><p>Prenatal smoke exposure, maternal obesity, aberrant fetal growth, and preterm birth are all risk factors for offspring metabolic syndrome. Cord blood <i>aryl-hydrocarbon receptor repressor</i> (<i>AHRR</i>) DNA methylation is responsive to maternal smoking during pregnancy. AHRR serves not only to inhibit <i>aryl-hydrocarbon receptor</i> (<i>AHR</i>) transcription, which is involved in mediating xenobiotic metabolism, but it is also involved in cell growth and differentiation. Other than maternal smoking, other predictors of offspring <i>AHRR</i> DNA methylation status remain unknown; we sought to identify them among newborns. We enrolled pregnant women in the PROGRESS birth cohort in Mexico City. Using pyrosequencing, we analyzed DNA methylation of 3 CpG sites within the <i>AHRR</i> gene promoter from the umbilical cord blood of 531 infants. We used generalized estimating equations to account for the correlation of DNA methylation between CpG sites. Multivariable models were used to adjust for maternal age, BMI, education, parity, smoke-exposure, infant sex, gestational age, and birth weight-for-gestational age. <i>AHRR</i> DNA methylation was positively associated with maternal BMI (<i>P</i> = 0.0009) and negatively associated with the length of gestation (<i>P</i> < 0.0001) and birth weight-for-gestational age (<i>P</i> < 0.0001). <i>AHRR</i> DNA methylation was 2.1% higher in offspring of obese vs. normal weight mothers and 3.1% higher in preterm vs. term infants, representing a third and a half standard deviation differences in methylation, respectively. In conclusion, offspring <i>AHRR</i> DNA methylation was associated with maternal obesity during pregnancy as well as infant gestational age and birth weight-for-gestational age. Further work to discover the health impacts of altered <i>AHRR</i> DNA methylation is warranted.</p></div

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Background: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. Methods: NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Findings: Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Funding: Bayer and Janssen