Faculty Bibliography

BACKGROUND AND OBJECTIVES:Infant weight patterns predict subsequent weight outcomes. Rapid infant weight gain, defined as a >0.67 increase in weight-for-age z-score (WAZ) between two time points in infancy, increases obesity risk. Higher oxidative stress, an imbalance between antioxidants and reactive oxygen species, has been associated with low birthweight and paradoxically also with later obesity. We hypothesized that prenatal oxidative stress may also be associated with rapid infant weight gain, an early weight pattern associated with future obesity. METHODS:Within the NYU Children's Health and Environment Study prospective pregnancy cohort, we analyzed associations between prenatal lipid, protein, and DNA urinary oxidative stress biomarkers and infant weight data. Primary outcome was rapid infant weight gain (>0.67 increase in WAZ) between birth and later infancy at the 8 or 12 month visit. Secondary outcomes included: very rapid weight gain (>1.34 increase in WAZ), low (<2500 g) or high (≥4000 g) birthweight, and low (< -1 WAZ) or high (>1 WAZ) 12 month weight. RESULTS:Pregnant participants consented to the postnatal study (n = 541); 425 participants had weight data both at birth and in later infancy. In an adjusted binary model, prenatal 8-iso-PGF2α, a lipid oxidative stress biomarker, was associated with rapid infant weight gain (aOR 1.44; 95% CI: 1.16, 1.78, p = 0.001). In a multinomial model using ≤0.67 change in WAZ as a reference group, 8-iso-PGF2α was associated with rapid infant weight gain (defined as >0.67 but ≤1.34 WAZ; aOR 1.57, 95% CI: 1.19, 2.05, p = 0.001) and very rapid infant weight gain (defined as >1.34 WAZ; aOR 1.33; 95% CI: 1.02, 1.72, p < 0.05) Secondary analyses detected associations between 8-iso-PGF2α and low birthweight outcomes. CONCLUSIONS:We found an association between 8-iso-PGF2α, a lipid prenatal oxidative stress biomarker, and rapid infant weight gain, expanding our understanding of the developmental origins of obesity and cardiometabolic disease.

On September 7 and 8, 2022, Healthy Environment and Endocrine Disruptors Strategies, an Environmental Health Sciences program, convened a scientific workshop of relevant stakeholders involved in obesity, toxicology, or obesogen research to review the state of the science regarding the role of obesogenic chemicals that might be contributing to the obesity pandemic. The workshop's objectives were to examine the evidence supporting the hypothesis that obesogens contribute to the etiology of human obesity; to discuss opportunities for improved understanding, acceptance, and dissemination of obesogens as contributors to the obesity pandemic; and to consider the need for future research and potential mitigation strategies. This report details the discussions, key areas of agreement, and future opportunities to prevent obesity. The attendees agreed that environmental obesogens are real, significant, and a contributor at some degree to weight gain at the individual level and to the global obesity and metabolic disease pandemic at a societal level; moreover, it is at least, in theory, remediable.

BACKGROUND:Epidemiological evidence for gestational polycyclic aromatic hydrocarbon (PAH) exposure and adverse child cognitive outcomes is mixed; little is known about critical windows of exposure. OBJECTIVE:We investigated associations between prenatal PAH exposure and child cognition in a large, multi-site study. METHODS:We included mother-child dyads from two pooled prospective pregnancy cohorts (CANDLE and TIDES, N = 1,223) in the ECHO-PATHWAYS Consortium. Seven urinary mono-hydroxylated PAH metabolites were measured in mid-pregnancy in both cohorts as well as early and late pregnancy in TIDES. Child intelligence quotient (IQ) was assessed between ages 4-6. Associations between individual PAH metabolites and IQ were estimated with multivariable linear regression. Interaction terms were used to examine effect modification by child sex and maternal obesity. We explored associations of PAH metabolite mixtures with IQ using weighted quantile sum regression. In TIDES, we averaged PAH metabolites over three periods of pregnancy and by pregnancy period to investigate associations between PAH metabolites and IQ. RESULTS: = 0.04). In analyses across pregnancy (TIDES-only), inverse associations with IQ were observed for 2-hydroxyphenanthrene averaged across pregnancy (β = -1.28 [95%CI:-2.53,-0.03]) and in early pregnancy (β = -1.14 [95%CI:-2.00,-0.28]). SIGNIFICANCE/CONCLUSIONS:In this multi-cohort analysis, we observed limited evidence of adverse associations of early pregnancy PAHs with child IQ. Analyses in the pooled cohorts were null. However, results also indicated that utilizing more than one exposure measures across pregnancy could improve the ability to detect associations by identifying sensitive windows and improving the reliability of exposure measurement. More research with multiple timepoints of PAH assessment is warranted.

Plastic pollution breaks a planetary boundary threatening wildlife and humans through its physical and chemical effects. Of the latter, the release of endocrine disrupting chemicals (EDCs) has consequences on the prevalence of human diseases related to the endocrine system. Bisphenols (BPs) and phthalates are two groups of EDCs commonly found in plastics that migrate into the environment and make low-dose human exposure ubiquitous. Here we review epidemiological, animal, and cellular studies linking exposure to BPs and phthalates to altered glucose regulation, with emphasis on the role of pancreatic β-cells. Epidemiological studies indicate that exposure to BPs and phthalates is associated with diabetes mellitus. Studies in animal models indicate that treatment with doses within the range of human exposure decreases insulin sensitivity and glucose tolerance, induces dyslipidemia, and modifies functional β-cell mass and serum levels of insulin, leptin, and adiponectin. These studies reveal that disruption of β-cell physiology by EDCs plays a key role in impairing glucose homeostasis by altering the mechanisms used by β-cells to adapt to metabolic stress such as chronic nutrient excess. Studies at the cellular level demonstrate that BPs and phthalates modify the same biochemical pathways involved in adaptation to chronic excess fuel. These include changes in insulin biosynthesis and secretion, electrical activity, expression of key genes, and mitochondrial function. The data summarized here indicate that BPs and phthalates are important risk factors for diabetes mellitus and support a global effort to decrease plastic pollution and human exposure to EDCs.

PURPOSE/OBJECTIVE:To evaluate whether underlying infertility and mode of conception are associated with childhood behavioral disorders. METHODS:Oversampling on fertility treatment exposure using vital records, the Upstate KIDS Study followed 2057 children (of 1754 mothers) from birth to 11 years. Type of fertility treatment and time to pregnancy (TTP) were self-reported. Mothers completed annual questionnaires reporting symptomology, diagnoses, and medications at 7-11 years of age. The information identified children with probable attention-deficit/hyperactivity disorder, anxiety or depression, and conduct or oppositional defiant disorders. We estimated adjusted relative risks (aRR) for disorders by underlying infertility (TTP > 12 months) or treatment exposure groups compared to children born to parents with TTP ≤ 12 months. RESULTS:Children conceived with fertility treatment (34%) did not have an increased risk of attention-deficit/hyperactivity disorder (aRR): 1.21; 95% CI: 0.88, 1.65), or conduct or oppositional defiant disorders (aRR: 1.31; 0.91, 1.86), but did have an increased risk of anxiety or depression (aRR: 1.63; 1.18, 2.24), which remained elevated even after adjusting for parental mood disorders (aRR: 1.40; 0.99, 1.96). Underlying infertility without the use of treatment was also associated with a risk of anxiety or depression (aRR: 1.82; 95% CI: 0.96, 3.43). CONCLUSIONS:Underlying infertility or its treatment was not associated with risk of attention-deficit/hyperactivity disorder. Observations of increased anxiety or depression require replication.

IMPORTANCE:Gender-diverse youths have higher rates of mental health problems compared with the general population, as shown in both clinical and nonclinical populations. Brain correlates of gender diversity, however, have been reported only among youths with gender dysphoria or in transgender individuals. OBJECTIVE:To examine brain morphologic correlates of gender diversity among adolescents from a general pediatric population who were assigned male or female at birth, separately. DESIGN, SETTING, AND PARTICIPANTS:This cross-sectional study was embedded in Generation R, a multiethnic population-based study conducted in Rotterdam, the Netherlands. Adolescents who were born between April 1, 2002, and January 31, 2006, and had information on self-reported or parent-reported gender diversity and structural neuroimaging at ages 13 to 15 years were included. Data analysis was performed from April 1 to July 31, 2022. EXPOSURES:Gender-diverse experiences among adolescents were measured with selected items from the Achenbach System of Empirically Based Assessment forms and the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults, as reported by adolescents and/or their parents. MAIN OUTCOMES AND MEASURES:High-resolution structural neuroimaging data were collected using a 3-T magnetic resonance imaging scanner (at a single site). We used linear regression models to examine differences in global brain volumetric measures between adolescents who reported gender diversity and those who did not. RESULTS:This study included 2165 participants, with a mean (SD) age of 13.8 (0.6) years at scanning. A total of 1159 participants (53.5%) were assigned female at birth and 1006 (46.5%) were assigned male at birth. With regard to maternal country of origin, 1217 mothers (57.6%) were from the Netherlands and 896 (42.4%) were from outside the Netherlands. Adolescents who reported gender diversity did not differ in global brain volumetric measures from adolescents who did not report gender diversity. In whole-brain, vertexwise analyses among adolescents assigned male at birth, thicker cortices in the left inferior temporal gyrus were observed among youths who reported gender diversity compared with those who did not. No associations were observed between gender diversity and surface area in vertexwise analyses. CONCLUSIONS AND RELEVANCE:The findings of this cross-sectional study suggest that global brain volumetric measures did not differ between adolescents who reported gender diversity and those who did not. However, these findings further suggest that gender diversity in the general population correlates with specific brain morphologic features in the inferior temporal gyrus among youths who are assigned male at birth. Replication of these findings is necessary to elucidate the potential neurobiological basis of gender diversity in the general population. Future longitudinal studies should also investigate the directionality of these associations.

BACKGROUND:In the US, the Food and Drug Administration (US FDA) is charged with protecting the safety of food from both pathogens and chemicals used in food production and food packaging. To protect the public in a transparent manner, the FDA needs to have an operational definition of what it considers to be an "adverse effect" so that it can take action against harmful agents. The FDA has recently published two statements where, for the first time, it defines the characteristics of an adverse effect that it uses to interpret toxicity studies. OBJECTIVE:In this brief review, we examine two recent actions by the FDA, a proposed rule regarding a color additive used in vegetarian burgers and a decision not to recall fish with high levels of scombrotoxin. We evaluated the FDA's description of the criteria used to determine which outcomes should be considered adverse. OVERVIEW/BACKGROUND:We describe three reasons why the FDA's criteria for "adverse effects" is not public health protective. These include an unscientific requirement for a monotonic dose response, which conflates hazard assessment and dose response assessment while also ignoring evidence for non-linear and non-monotonic effects for many environmental agents; a requirement that the effect be observed in both sexes, which fails to acknowledge the many sex- and gender-specific effects on physiology, disease incidence and severity, and anatomy; and a requirement that the effects are irreversible, which does not acknowledge the role of exposure timing or appreciate transgenerational effects that have been demonstrated for environmental chemicals. CONCLUSIONS:The FDA's criteria for identifying adverse effects are inadequate because they are not science-based. Addressing this is important, because the acknowledgement of adverse effects is central to regulatory decisions and the protection of public health.

CONTEXT/BACKGROUND:Manganese (Mn) exposure is prevalent, as it is found naturally as ionized trace elements and released into the environment as a byproduct of manufacturing and waste disposal. Animal and human studies have suggested variable effects on thyroid function, but the association of Mn exposure with thyroid function has not been evaluated in a national sample. OBJECTIVE:To investigate the associations between serum and urinary Mn levels and serum thyroid hormone concentrations in a nationally representative sample. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION/METHODS:This was a cross-sectional analysis of data from the 2011-2012 National Health and Nutrition Examination Survey among 1360 participants. MAIN OUTCOME MEASURES/METHODS:Serum thyroid stimulating hormone (TSH), total triiodothyronine (T3), total thyroxine (T4), free T3, and free T4. RESULTS:Serum Mn levels were positively associated with increasing total T4, free T3, and total T3 in the whole cohort (p < 0.01). Urinary Mn levels were not associated with thyroid hormone levels. When subgroup analyses were performed by gender, only males had total T4 associated with serum Mn [β = 0.01, p < 0.01, confidence interval (CI): 0.004-0.018]. In individuals under 22 years old, serum Mn was significantly associated with total T4 (β = 0.02, p = 0.002, CI: 0.008-0.029). Serum Mn was positively associated with Free T3 in both genders (β = 0.07, p < 0.001). CONCLUSION/CONCLUSIONS:While our findings do not suggest clinical thyroid dysfunction, there is an association between serum Mn and subclinical changes in thyroid function that warrant further studies. Regulatory action should be considered as Mn-based organometallic compounds are being considered as replacements for lead in gasoline and may pose future risks to human health.

BACKGROUND:Bisphenols and phthalates are high production volume chemicals used as additives in a variety of plastic consumer products leading to near ubiquitous human exposure. These chemicals have established endocrine disrupting properties and have been linked to a range of adverse reproductive and developmental outcomes. Here, we investigated exposure in relation to fetal growth. METHODS:Participants included 855 mother-fetal pairs enrolled in the population-based New York University Children's Health and Environment Study (NYU CHES). Bisphenols and phthalates were measured in maternal urine collected repeatedly during pregnancy. Analyses included 15 phthalate metabolites and 2 bisphenols that were detected in 50 % of participants or more. Fetal biometry data were extracted from electronic ultrasonography records and estimated fetal weight (EFW) was predicted for all fetuses at 20, 30, and 36 weeks gestation. We used quantile regression adjusted for covariates to model exposure-outcome relations across percentiles of fetal weight at each gestational timepoint. We examined sex differences using stratified models. RESULTS:Few statistically significant associations were observed across chemicals, gestational time periods, percentiles, and sexes. However, within gestational timepoints, we found that among females, the molar sums of the phthalates DiNP and DnOP were generally associated with decreases in EFW among smaller babies and increases in EFW among larger babies. Among males, the opposite trend was observed. However, confidence intervals were generally wide at the tails of the distribution. CONCLUSION/CONCLUSIONS:In this sample, exposure to bisphenols and phthalates was associated with small sex-specific shifts in fetal growth; however, few associations were observed at the median of fetal weight and confidence intervals in the tails were wide. Findings were strongest for DiNP and DnOP, which are increasingly used as replacements for DEHP, supporting the need for future research on these contaminants.