Barrett M. Welch

Background: Inflammation is a common pathological feature underlying type 2 diabetes (T2D) risk and progression. Determining the roles of fatty acids and bioactive lipid oxylipin inflammatory mediators could inform T2D preventative efforts and therapeutic targets. Methods: Leveraging the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we evaluated cross-sectional and prospective associations of 81 oxylipins and polyunsaturated, monounsaturated, and saturated fatty acids with T2D. We assessed whether fatty acid levels differed at visit 2 by visit 1-prevalent T2D status and prioritized likely causal metabolites using Bayesian model averaging Mendelian randomization (MR-BMA). Results: Fifty-four fatty acids and oxylipins were associated with prevalent T2D at visit 1 (15,138 participants; 2,962 T2D cases), four of which (adrenic, dihomo-gamma-linolenic, tricosanoic, and lignoceric acids) were also associated with incident T2D by visit 2 (8,548 participants; 1,376 T2D events), though effects were attenuated for adrenic and dihomo-gamma-linolenic acids upon further adjustment for impaired glucose tolerance. Sixteen out of 28 fatty acids were significantly different at visit 2 between those with and without prevalent T2D at visit 1 (9,115 participants; 2,151 T2D cases), holding visit 1-measured fatty acid levels constant. MR-BMA prioritized one diHETrE oxylipin as a likely causal risk factor for T2D. Conclusions: Fatty acids and oxylipins showed complex patterns of association with T2D, including more associations likely reflecting overt disease processes in prevalent T2D, than incident risk-enhancing associations.

Prenatal exposure to phthalates has been associated with several pregnancy and developmental end points, including birthweight, and may be harmful to fetal growth across pregnancy and not only at birth. Therefore, this study investigates associations between environmental exposure to phthalates and their replacements, individually and as mixtures, with ultrasound and delivery measures of fetal growth. This study leverages data from the LIFECODES Fetal Growth Study, a case-cohort study (N = 900) selected from an ongoing prospective pregnancy cohort at Brigham and Women’s Hospital (BWH). Pregnant women were eligible for inclusion in the parent cohort if they were at least 18 years of age, were recruited prior to 15 weeks gestation, and intended to deliver at BWH. Selection into the case-cohort was restricted to nonanomalous singleton pregnancies that ended in a live birth. Biomarkers of exposure to phthalate and replacement metabolites were quantified in samples from three time points across pregnancy (median 10, 26, and 35 weeks gestation) and examined individually and as mixtures. The main outcomes were small-for-gestational-age (SGA, birthweight 90th percentile). Associations with repeated ultrasound measures of fetal growth and birthweight z-scores were also assessed. As a secondary analysis, associations with phenotypes of SGA and LGA births based on patterns of prenatal growth were examined. We report that the LMW phthalate mixture was inversely associated with ultrasound measures of fetal growth as well as birth weight among male fetuses. Conversely, certain HMW phthalates were associated with higher ultrasound measures among female fetuses. Similar patterns of effect were observed for associations with SGA and LGA birth, but confidence intervals crossed the null. When associations with phenotypes of growth were examined, many individual phthalate biomarkers were associated with increased odds of belonging in a group with a phenotype late-pregnancy growth restriction. This study demonstrated that ultrasound measures provided evidence of associations that were absent when using measures at birth. Notably, phthalates were associated with a specific phenotype of SGA birth characterized by late-pregnancy growth restriction. These findings support biological effects of phthalate exposure in utero that may have long-term consequences to the developing fetus.

Background: Gestational weight gain (GWG), the maternal weight gained between pre‐pregnancy and delivery, is an important risk factor for adverse maternal and infant health outcomes. In 1990, the National Academy of Medicine released GWG recommendations based on pre‐pregnancy body mass index (BMI). These guidelines were revised in 2009, yet few studies have assessed temporal trends in GWG following the change. Objectives: To evaluate temporal trends in total GWG within a large, ongoing pregnancy cohort. Methods: We used data from a prospective cohort in Boston, Massachusetts, of 3675 participants with deliveries between 2007 and 2019. Using 29,037 serial weight measures (median = 7/participant), we fit mixed‐effect models to predict weight at delivery. Total GWG (kg) was defined as the difference between the model‐predicted weight at delivery and self‐reported pre‐pregnancy weight. We categorised GWG as below, within or above the 2009 BMI‐specific guidelines. We analysed proportional trends in GWG categories: (a) overall and (b) stratified by maternal characteristics (pre‐pregnancy BMI, race/ethnicity, educational level and parity). We analysed trends in covariate‐adjusted geometric mean (GMs) of GWG using multiple linear regression. Results: The proportion of participants gaining weight within the GWG guidelines decreased from 46% in 2007–2008 to 24% in 2018–2019, which was driven by an increase in those gaining above the guidelines (40% to 73%). Across maternal characteristics, the largest increases of proportions above the guidelines were among those of normal pre‐pregnancy BMI (19% to 62%) and of non‐Hispanic Black (48% to 85%) or non‐Hispanic White (37% to 74%) race/ethnicity. Consistently, GMs increased from 8.3 kg (95% confidence interval [CI] 6.3, 10.8) in 2007–2008 to 10.9 kg (95% CI 7.9, 14.9) in 2018–2019. Conclusions: Results from this large cohort study provide evidence that fewer women have been meeting the revised GWG guidelines and more have been gaining above the recommendations.

Consumer product chemicals pose an environmental risk to public health. Exposure during pregnancy to consumer product chemicals, particularly phthalates and phenols, may increase the susceptibility to pregnancy disorders by dysregulating inflammation and oxidative stress. However, existing studies rely on downstream and nonmodifiable markers of these processes. Oxylipins are oxidized lipids that act as key upstream drivers of inflammation and oxidative stress. Importantly, oxylipins are responsive to therapeutic interventions and thus potentially modifiable. Using recent advances in lipidomics and statistical approaches to address both individual chemical biomarkers and their mixtures, we determined associations between early pregnancy biomarkers of consumer product chemical exposure and oxylipins in a large prospective cohort. Overall, our results revealed associations among oxylipins produced across several biosynthetic pathways, suggesting a pattern indicative of dysregulated inflammation and elevated levels of oxidative stress. Phthalate metabolites were the primary drivers of associations, particularly for metabolites of low molecular weight phthalates, often used in personal care products. However, we found similar associations for a biomarker of a phthalate replacement that is increasingly used in consumer products. Our study provides observational evidence of specific physiological pathways that may be dysregulated by exposure to consumer product chemicals, including legacy phthalates and phthalate replacements.