Faculty Bibliography

BACKGROUND:Exposure to phthalates is ubiquitous across the United States. While phthalates have anti-androgenic effects in men, there is little research on their potential impacts on sex hormone concentrations in women and that also take into account menopausal status. METHODS:Cross-sectional data on urinary phthalate metabolites, serum sex hormones, and relevant covariates were obtained from the National Health and Nutrition Examination Survey 2013-14 and 2015-16. Women over the age of 20 who were not pregnant or breastfeeding and had not undergone oophorectomy were included (n = 698 premenopausal, n = 557 postmenopausal). Weighted multivariable linear and Tobit regression models stratified by menopausal status were fit with natural log-transformed phthalate concentrations and sex hormone outcomes adjusting for relevant covariates. RESULTS:Phthalate metabolites were associated with differences in sex hormone concentrations among postmenopausal women only. Di-2-ethylhexyl phthalate (DEHP) was associated with lower serum estradiol and bioavailable testosterone concentrations. Specifically, a doubling of DEHP concentrations was associated with 5.9% (95% Confidence Interval (CI): 0.2%, 11.3%) lower estradiol and 6.2% (95% CI: 0.0%, 12.1%) lower bioavailable testosterone concentrations. In contrast, 1,2-cyclohexane dicarboxylic acid di-isononyl ester (DINCH) was associated with higher free testosterone, bioavailable testosterone, and free androgen index. Finally, di-2-ethylhexyl terephthalate (DEHTP) was associated with a higher testosterone-to-estradiol ratio. None of these results retained statistical significance when adjusted for multiple comparisons. CONCLUSIONS:DEHP, DINCH, and DEHTP were associated with differences in serum sex hormone concentrations among postmenopausal women, highlighting the need for further research into the safety of these chemicals.

Maternal diet, prior to and during pregnancy, plays an important role in the immediate and long-term health of the mother and her offspring. Our objectives were to assess diet quality among a large, diverse, urban cohort of pregnant women, and examine associations with sociodemographic and health behavior characteristics. Data were from 1,325 pregnant women enrolled in New York University Children's Health and Environment Study (NYU CHES). Diet quality was assessed using the Healthy Eating Index (HEI)-2015. Mean total HEI-2015 score was 74.9 (SD = 8.5); 376 (28%), 612 (46%), 263 (20%), and 74 (6%) of women had scores that fell into the grade range of A/B, C, D, and F, respectively. Mean HEI-2015 component scores were high for fruit and whole grains and low for protein-related, sodium, and fat-related components. In multivariable linear regression models, Hispanic women scored 1.65 points higher on the total HEI-2015 (95% CI: 0.21, 3.10) compared to non-Hispanic White women, while younger age (<30 years), parity, single status, pre-pregnancy obesity, smoking, pre-existing hypertension, moderate/severe depressive symptoms, not meeting physical activity recommendations, and not taking a vitamin before pregnancy were associated with ~1.5-5-point lower mean total HEI-2015 scores. Diet is a modifiable behavior; our results suggest a continued need for pre-conceptional and prenatal nutritional counseling.

Since reports published in 2015 and 2016 identified 15 probable exposure-outcome associations, there has been an increase in studies in humans of exposure to endocrine-disrupting chemicals (EDCs) and a deepened understanding of their effects on human health. In this Series paper, we have reviewed subsequent additions to the literature and identified new exposure-outcome associations with substantial human evidence. Evidence is particularly strong for relations between perfluoroalkyl substances and child and adult obesity, impaired glucose tolerance, gestational diabetes, reduced birthweight, reduced semen quality, polycystic ovarian syndrome, endometriosis, and breast cancer. Evidence also exists for relations between bisphenols and adult diabetes, reduced semen quality, and polycystic ovarian syndrome; phthalates and prematurity, reduced anogenital distance in boys, childhood obesity, and impaired glucose tolerance; organophosphate pesticides and reduced semen quality; and occupational exposure to pesticides and prostate cancer. Greater evidence has accumulated than was previously identified for cognitive deficits and attention-deficit disorder in children following prenatal exposure to bisphenol A, organophosphate pesticides, and polybrominated flame retardants. Although systematic evaluation is needed of the probability and strength of these exposure-outcome relations, the growing evidence supports urgent action to reduce exposure to EDCs.

CONTEXT/BACKGROUND:Phthalates are commonly found in commercial packaging, solvents, vinyl, and personal care products, and there is concern for potential endocrine-disrupting effects in males. The commonly used di-2-ethylhexyl phthalate (DEHP) has progressively been replaced by seldom studied compounds, such as bis-2-ethylhexyl terephthalate and 1,2-cyclohexane dicarboxylic acid di-isononyl ester (DINCH). OBJECTIVE:To investigate the associations between the urinary phthalate metabolites and serum sex steroid hormone concentrations in a nationally representative sample of adult males. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION/UNASSIGNED:This was a cross-sectional analysis of data from the 2013-2016 National Health and Nutrition Examination Survey among 1420 male participants aged ≥20 years. MAIN OUTCOME MEASURES/METHODS:Serum levels of total testosterone, estradiol, sex hormone binding globulin, and derived sex hormone measurements of free testosterone, bioavailable testosterone, and free androgen index were examined as log-transformed continuous variables. RESULTS:Phthalate metabolites were not statistically significantly associated with sex hormone concentrations among all men. However, associations varied by age. High molecular weight phthalates were associated with lower total, free, and bioavailable testosterone among men age ≥60. Specifically, each doubling of ΣDEHP was associated with 7.72% lower total testosterone among older men (95% Confidence Interval: -12.76%, -2.39%). Low molecular phthalates were associated with lower total, free, and bioavailable testosterone among men age 20-39 and ΣDINCH was associated with lower total testosterone among men age ≥40. CONCLUSIONS:Our results indicate that males may be vulnerable to different phthalate metabolites in age-specific ways. These results support further investigation into the endocrine-disrupting effects of phthalates.

The aims of the NYU Children's Health and Environment Study (CHES) are to evaluate influences of prenatal non-persistent chemical exposures on fetal and postnatal growth and pool our data with the US National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Program to answer collaborative research questions on the impact of the preconceptual, prenatal, and postnatal environment on childhood obesity, neurodevelopment, pre/peri/postnatal outcomes, upper and lower airway outcomes, and positive health. Eligible women were ≥ 18 years old, < 18 weeks pregnant, had a pregnancy that is not medically threatened, and planned to deliver at NYU Langone Hospital-Manhattan, Bellevue Hospital, or NYU Langone Hospital-Brooklyn. Between March 22, 2016 and April 15, 2019, we recruited 2469 pregnant women, from whom 2193 completed an initial questionnaire and continued into NYU CHES. Of the 2193, 88 miscarried, 28 terminated, and 20 experienced stillbirth, while 57 were lost to follow up. We report here demographic and other characteristics of the 2000 live deliveries (2037 children), from whom 1624 (80%) consented to postnatal follow-up. Data collection in pregnancy was nested in clinical care, with questionnaire and specimen collection conducted during routine prenatal visits at < 18, 18-25, and > 25 weeks gestation. These have been followed by questionnaire and specimen collection at birth and regular postpartum intervals.

BACKGROUND:Maternal obesity and high gestational weight gain (GWG) disproportionally affect low-income populations and may be associated with child neurodevelopment in a sex-specific manner. We examined sex-specific associations between prepregnancy BMI, GWG, and child neurodevelopment at age 7. METHODS:Data are from a prospective low-income cohort of African American and Dominican women (n = 368; 44.8% male offspring) enrolled during the second half of pregnancy from 1998 to 2006. Neurodevelopment was measured using the Wechsler Intelligence Scale for Children (WISC-IV) at approximately child age 7. Linear regression estimated associations between prepregnancy BMI, GWG, and child outcomes, adjusting for race/ethnicity, marital status, gestational age at delivery, maternal education, maternal IQ and child age. RESULTS:Overweight affected 23.9% of mothers and obesity affected 22.6%. At age 7, full-scale IQ was higher among girls (99.7 ± 11.6) compared to boys (96.9 ± 13.3). Among boys, but not girls, prepregnancy overweight and obesity were associated with lower full-scale IQ scores [overweight β: - 7.1, 95% CI: (- 12.1, - 2.0); obesity β: - 5.7, 95% CI: (- 10.7, - 0.7)]. GWG was not associated with full-scale IQ in either sex. CONCLUSIONS:Prepregnancy overweight and obesity were associated with lower IQ among boys, but not girls, at 7 years. These findings are important considering overweight and obesity prevalence and the long-term implications of early cognitive development.

BACKGROUND:Studies of body mass index and semen quality have reported mixed results, but almost all were cross-sectional and many were conducted in selected populations. Longitudinal studies in population-based cohorts are necessary to identify how timing and duration of excess adiposity may affect semen quality. METHODS:In 193 members of the Child Health and Development Studies birth cohort, we examined associations of birth weight and adiposity at six time points spanning early childhood and adulthood with sperm concentration, motility, and morphology at mean age 44 years, as well as with corresponding 2010 World Health Organization (WHO) subfertility reference levels. RESULTS:Birth weight for gestational age percentile was positively associated with square-root sperm concentration (regression coefficient B [95% confidence interval] = 0.02 × 103 sperm/ml [0.004, 0.04]). Overweight/obesity in men's 20s was associated with lower percent progressive motility (B =-5.2 [-9.9, -0.63]), higher odds of low motility (odds ratio (OR) = 2.4 [1.3, 4.4]), and higher odds of poor morphology (OR = 1.9 [0.94, 3.8]). Those who were overweight/obese in their 20s were also more likely to meet two or three WHO subfertility criteria (OR = 3.9 [1.6, 9.4]) compared with normal-weight men. Each additional adult decade in which a participant was overweight/obese was associated with higher odds of low motility (OR = 1.3 [0.96, 1.6]) and higher odds of meeting two or three WHO subfertility criteria (OR = 1.5 [1.0, 2.2]). CONCLUSIONS:In our data, associations among adiposity and sperm concentration, motility, and morphology varied according to timing and duration of exposure, potentially reflecting different biological mechanisms that influence these semen parameters.

Despite advances in the field of male reproductive health, idiopathic male infertility, in which a man has altered semen characteristics without an identifiable cause and there is no female factor infertility, remains a challenging condition to diagnose and manage. Increasing evidence suggests that oxidative stress (OS) plays an independent role in the etiology of male infertility, with 30% to 80% of infertile men having elevated seminal reactive oxygen species levels. OS can negatively affect fertility via a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm's potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause.

STUDY QUESTION/OBJECTIVE:Are early-pregnancy urinary bisphenol and phthalate metabolite concentrations associated with placental function markers, blood pressure (BP) trajectories during pregnancy and risk of gestational hypertensive disorders? SUMMARY ANSWER/UNASSIGNED:Early-pregnancy bisphenols and phthalate metabolites were not consistently associated with maternal BP changes or gestational hypertensive disorders, but subclinical, statistically significant associations with placental angiogenic markers and placental hemodynamics were identified. WHAT IS KNOWN ALREADY/UNASSIGNED:In vitro studies suggest that bisphenols and phthalate metabolites may disrupt early placental development and affect the risk of gestational hypertensive disorders. Previous studies investigating effects of bisphenols and phthalate metabolites on gestational hypertensive disorders reported inconsistent results and did not examine placental function or BP throughout pregnancy. STUDY DESIGN, SIZE, DURATION/UNASSIGNED:In a population-based prospective cohort study, bisphenol and phthalate metabolite concentrations were measured in a spot urine sample in early pregnancy among 1396 women whose children participated in postnatal follow-up measurements. PARTICIPANTS/MATERIALS, SETTING, METHODS/UNASSIGNED:After exclusion of women without any BP measurement or with pre-existing hypertension, 1233 women were included in the analysis. Urinary bisphenol and phthalate metabolite concentrations were measured in early-pregnancy [median gestational age 13.1 weeks, inter-quartile range 12.1-14.5]. Molar sums of total bisphenols and of low molecular weight phthalate, high molecular weight (HMW) phthalate, di-2-ethylhexylphthalate, and di-n-octylphthalate metabolites were calculated. Placental angiogenic markers (placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt)-1), placental hemodynamic function measures (umbilical artery pulsatility index (PI), uterine artery resistance index (RI), notching and placental weight), and maternal BP were measured in different trimesters. Information on gestational hypertensive disorders was obtained from medical records. MAIN RESULTS AND THE ROLE OF CHANCE/UNASSIGNED:Each log unit increase in HMW phthalate metabolites was associated with a 141.72 (95% CI: 29.13, 373.21) higher early pregnancy sFlt-1/PlGF ratio (range in total sample 9-900). This association was driven by mono-[(2-carboxymethyl)hexyl]phthalate. In the repeated measurements regression models, each log unit increase in bisphenol A was associated with a 0.15 SD (95% CI: 0.03, 0.26) higher intercept and -0.01 SD (95% CI: -0.01, -0.00) decreasing slope of the umbilical artery PI Z-score and a -1.28 SD (95% CI: -2.24, -0.33) lower intercept and 0.06 SD (95% CI: 0.02, 0.11) increasing slope of the uterine artery RI Z-score. These associations remained significant after Bonferroni correction. Early-pregnancy bisphenols or phthalate metabolites showed no consistent associations with any other outcome. LIMITATIONS, REASONS FOR CAUTION/UNASSIGNED:Information on a large number of potential confounders was available but was partly self-reported. Bisphenols and phthalate metabolites, which typically have a half-life of 24-48 h, were measured via single spot urine samples in early-pregnancy. In addition, at the current sample size, the study was powered to detect an odds ratio of 1.57 for gestational hypertension and 1.78 for pre-eclampsia, but was underpowered to perform multivariable analyses for these outcomes. Further studies combining data from different cohorts may be necessary to increase power. These limitations are possible sources of non-differential misclassification leading to bias toward the null. WIDER IMPLICATIONS OF THE FINDINGS/UNASSIGNED:Bisphenols and phthalate metabolites were not associated with longitudinal changes in BP in pregnancy in our low-risk population. The observed subclinical associations of phthalates with the sFlt-1/PlGF ratio and of bisphenol A with placental hemodynamics may contribute to adverse pregnancy outcomes. Our results are therefore more supportive of an association of early pregnancy bisphenols and phthalate metabolites with risk for pre-eclampsia than with gestational hypertension. STUDY FUNDING/COMPETING INTEREST(S)/UNASSIGNED:This analysis was supported by Grant (ES022972) from the National Institutes of Health, USA. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health. The authors report no conflicts of interest.

BACKGROUND:Exposure to non-persistent chemicals in consumer products is ubiquitous and associated with endocrine-disrupting effects. These effects have been linked to infertility and adverse pregnancy outcomes in some studies and could affect couple fecundability, i.e. the capacity to conceive a pregnancy, quantified as time to pregnancy (TTP). OBJECTIVE AND RATIONALE/UNASSIGNED:Few epidemiologic studies have examined the impact of non-persistent chemicals specifically on TTP, and the results of these studies have not been synthesized. We undertook a systematic review to summarize the strength of evidence for associations of common non-persistent chemicals with couple fecundability and to identify gaps and limitations in the literature, with the aim of informing policy decisions and future research. SEARCH METHODS/METHODS:We performed an electronic search of English language literature published between 1 January 2007 and 25 August 2017 in MEDLINE, EMBASE.com, Global Health, DART/TOXLINE, POPLINE and DESTAF. We included human retrospective and prospective cohort, cross-sectional and case-control studies that examined phthalates, bisphenol A, triclosan, triclocarban, benzophenones, parabens and glycol ethers in consumer products, and considered TTP or fecundability as an outcome among women, men and couples conceiving without medical assistance. We excluded editorials, opinion pieces, introductions to special sections, articles that described only lifestyle (e.g. caffeine, stress) or clinical factors (e.g. semen parameters, IVF success). Standardized forms for screening, data extraction and study quality were developed using DistillerSR software and completed in duplicate. We used the Newcastle-Ottawa Scale to assess risk of bias and devised additional quality metrics based on specific methodological features of fecundability studies. OUTCOMES/RESULTS:The search returned 3456 articles. There were 15 papers from 12 studies which met inclusion criteria, of which eight included biomarkers of chemical exposure. Studies varied widely in terms of exposure characterization, precluding a meta-analytic approach. Among the studies that measured exposure using biospecimens, results were equivocal for associations between either male or female phthalate exposure and TTP. There was preliminary support for associations of female exposure to some parabens and glycol ethers and of male exposure to benzophenone with longer TTP, but further research and replication of these results are needed. The results provided little to no indication that bisphenol A, triclocarban or triclosan exposure was associated with TTP. WIDER IMPLICATIONS/UNASSIGNED:Despite a growing literature on couple exposure to non-persistent endocrine-disrupting chemicals and fecundability, evidence for associations between biologically measured exposures and TTP is limited. Equivocal results with different non-persistent chemical compounds and metabolites complicate the interpretation of our findings with respect to TTP, but do not preclude action, given the documented endocrine disrupting effects on other reproductive outcomes as well as fetal development. We therefore advocate for common-sense lifestyle changes in which both females and males seeking to conceive minimize their exposure to non-persistent chemicals. SYSTEMATIC REVIEW REGISTRATION NUMBER/UNASSIGNED:CRD42018084304.