The association between urinary glyphosate and aminomethyl phosphonic acid with biomarkers of oxidative stress among pregnant women in the PROTECT birth cohort study.

BACKGROUND: Glyphosate is a widely used herbicide in global agriculture. Glyphosate and its primary environmental degradate, aminomethyl phosphonic acid (AMPA), have been shown to disrupt endocrine function and induce oxidative stress in in vitro and animal studies. To our knowledge, these relationships have not been previously characterized in epidemiological settings. Elevated urinary levels of glyphosate and AMPA may be indicative of health effects caused by previous exposure via multiple mechanisms including oxidative stress. METHODS: Glyphosate and AMPA were measured in 347 urine samples collected between 16 and 20 weeks gestation and 24-28 weeks gestation from pregnant women in the PROTECT birth cohort. Urinary biomarkers of oxidative stress, comprising 8-isoprostane-prostaglandin-F2α (8-iso-PGF2α), its metabolite 2,3-dinor-5,6-dihydro-15-F2 t-isoprostane (8-isoprostane metabolite) and prostaglandin-F2α (PGF2α), were also measured. Linear mixed effect models assessed the association between exposures and oxidative stress adjusting for maternal age, smoking status, alcohol consumption, household income and specific gravity. Potential nonlinear trends were also assessed using tertiles of glyphosate and AMPA exposure levels. RESULTS: No significant differences in exposure or oxidative stress biomarker concentrations were observed between study visits. An interquartile range (IQR) increase in AMPA was associated with 9.5% (95% CI: 0.5-19.3%) higher 8-iso-PGF2α metabolite concentrations. Significant linear trends were also identified when examining tertiles of exposure variables. Compared to the lowest exposure group, the second and third tertiles of AMPA were significantly associated with 12.8% (0.6-26.5%) and 15.2% (1.8-30.3%) higher 8-isoprostane metabolite, respectively. An IQR increase in glyphosate was suggestively associated with 4.7% (-0.9 to 10.7%) higher 8-iso-PGF2α. CONCLUSIONS: Urinary concentrations of the main environmental degradate of glyphosate, AMPA, were associated with higher levels of certain oxidative stress biomarkers. Associations with glyphosate reflected similar trends, although findings were not as strong. Additional research is required to better characterize the association between glyphosate exposure and biomarkers of oxidative stress, as well as potential downstream health consequences.

Prenatal exposure to the herbicide 2,4-D is associated with deficits in auditory processing during infancy.

INTRODUCTION: Despite widespread use, many herbicides and fungicides are not well studied for neurological effects. Fetal and infant brains are rapidly developing, yet the effects of early-life exposure to these classes of pesticides on visual and auditory function are unknown. Here we examined the effects of prenatal herbicide and fungicide exposure on infant grating visual acuity (VA) and auditory brainstem response (ABR). METHODS: 9 herbicides and 13 fungicides were measured in umbilical cord blood plasma from a cohort of infants in Fuyang County, China (n = 232). Grating VA and ABR latencies for waves I, III, V were measured at 3 time points: 6 weeks, 9 months, and 18 months. Outcomes included VA score, ABR wave V latency and ABR central conduction time (CCT [wave V- wave I]). Pesticides were analyzed as 3-level ordinal (non-detect [ND]/medium/high), or dichotomous (ND/detect), depending on detection rates. Linear mixed models were used to evaluate relations between pesticides and VA and ABR outcomes. RESULTS: 2,4-dichloroacetic acid (2,4-D), prometryn, simazine, and tetrahydrophthalamide (THPI, a metabolite of captan) were detected in 27%, 81%, 17%, and 16% of samples, respectively. Infants prenatally exposed to 2,4-D had slower auditory response times at 6 weeks. Infants with cord levels of 2,4-D > 1.17 ng/mL had wave V latencies that were 0.12 (95% CI: 0.03, 0.22) ms slower (p = 0.01) and overall CCTs that were 0.15 (95% CI:0.05, 0.25) ms slower (p = 0.003) than infants with non-detectable 2,4-D in their cord blood. No other statistically significant findings were observed for the other herbicides and fungicides or for the grating VA outcome. CONCLUSIONS: Prenatal exposure to the herbicide 2,4-D was associated with slower auditory signal transmission in early infancy. ABR latencies reflect auditory pathway maturation and longer latencies may indicate delayed auditory development.

Low-level prenatal lead exposure and infant sensory function.

BACKGROUND: Lead is a pervasive neurotoxicant that has been associated with poorer cognitive, behavioral, and motor outcomes in children. The effects of lead on sensory function have not been well characterized. The aim of this study was to assess the effects of prenatal lead exposure on infant sensory function, as measured by auditory brainstem response (ABR) and grating visual acuity (VA). METHODS: Lead was measured in maternal blood in mid- and late-pregnancy (mean gestational age = 15.5 and 39.0 weeks, respectively) and umbilical cord blood in a cohort of full-term infants in rural northeastern China. ABR latencies (peaks I, III, V) were measured in newborns during unsedated sleep (n = 315). The ABR central-to-peripheral (C-P) ratio was calculated as the ratio between the III-V and I-III interpeak intervals. VA was measured in 6-week-olds using Teller Acuity Cards (n = 1019) and assigned as the narrowest grid the infant fixated on. Multivariate linear regression was used to evaluate relationships between tertiles of mid-pregnancy, late-pregnancy, or cord lead and newborn ABR or 6-week VA. RESULTS: Higher late-pregnancy lead levels were associated with higher ABR C-P ratios and lower VA. In covariate-adjusted analyses, mean C-P ratios were 4.6 and 3.2 % higher in infants whose mothers had lead > 3.8 µg/dL and lead = 2-3.8 µg/dL, respectively, than for infants whose mothers had lead < 2 µg/dL (p-trend =0.002). In adjusted analyses for VA, mean scores were 8.5 and 7.2 % lower for maternal lead > 3.8 µg/dL and lead = 2-3.8 µg/dL, respectively, compared to lead < 2 µg/dL (p-trend =0.009). CONCLUSION: Auditory and visual systems maturation appears delayed in infants with higher prenatal lead exposure during late-pregnancy, even at relatively low levels. Both systems start myelinating in late gestation and mature rapidly in infancy. Higher ABR C-P ratio and lower grating VA scores suggest effects of low-level lead exposure on sensory system myelination.

Blood cadmium is elevated in iron deficient U.S. children: a cross-sectional study.

BACKGROUND: Cadmium (Cd), a widespread environmental contaminant, and iron deficiency (ID), the most common nutrient deficiency in the world, are known risk factors for neurodevelopmental delays, as well as other disorders, in infants and children. Studies assessing the cumulative effects of these factors are lacking in children, despite concerns of increased uptake of metals in the presence of ID. Here we sought to determine if blood and urine Cd levels were elevated in ID children compared to non-ID children. METHODS: Data for 5224 children, aged 3-19 years, were obtained from the 1999-2002 NHANES. ID was defined as ≥2 of 3 abnormal iron indicators (low serum ferritin [SF], high free erythrocyte protoporphyrin [FEP], low % transferrin saturation [TSAT]); ID anemia (IDA) was defined as ID plus low hemoglobin (Hgb). Logistic regression was used to evaluate associations between ID, IDA, and abnormal iron indicators and categories of blood and urine Cd. RESULTS: Adjusted odds of ID, IDA, low SF, and low TSAT were associated with increasing category of blood Cd but not urine Cd. Adjusted ORs (95% CI) for blood Cd ≥0.5 µg/L versus < LOD were = 1.74 (1.30-2.34), 4.02 (1.92-8.41), 4.08 (2.36-5.89) and 1.78 (1.32-2.39), for ID, IDA, low SF, and low TSAT, respectively. Age and sex specific analyses of blood Cd and ID/abnormal iron indicators revealed that the observed associations were strongest in females aged 16-19 years. CONCLUSIONS: Given their shared neurotoxic effects in children, and that many people live in areas with high burdens of both ID and Cd, more research into the complex relationships between nutrient deficiencies and environmental toxicants is vital.

Comparing the burden of illness in patients with alopecia areata vs atopic dermatitis in the US population from a payer perspective.

BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by nonscarring hair loss. AA frequently co-occurs with other inflammatory autoimmune conditions, presenting a significant clinical burden. OBJECTIVE: To compare the burden of illness, direct and indirect costs in adult patients with AA vs atopic dermatitis (AD). METHODS: This retrospective cohort study used US administrative claims data from the Merative MarketScan Commercial Claims and Encounters Database to compare commercially insured adults with AA to those with AD. Patients with an AA diagnosis between January 2017 and September 2019 were propensity score matched to patients with AD. Comorbidity burden, medication use, health care resource utilization, health care costs, and indirect costs during a 12-month follow-up period were compared between cohorts. RESULTS: Overall, 25,446 adult patients with AA were selected for the matched analysis with the AD cohort. Patients with AA generally had lower comorbidity burden than patients with AD; mean Deyo-Charlson Comorbidity Index scores were 0.36 (SD = 0.99) and 0.39 (SD = 0.92), for AA and AD, respectively (P = 0.007). Patients with AA had significantly lower proportions of allergic rhinitis, asthma, pruritus, skin infections, and urticaria, but higher proportions of thyroid disease, when compared with patients with AD (all P < 0.001). A smaller proportion of patients with AA had prescriptions for topical (45.3% vs 64.8%; P < 0.001) and oral (20.3% vs 29.6%; P < 0.001) corticosteroids and antianxiety and/or antidepressants (24.7% vs 29.7%; P < 0.001), but a significantly larger proportion for intralesional corticosteroids (triamcinolone) (49.6% vs 21.7%; P < 0.001), compared with patients with AD. Despite a lower comorbidity burden and generally less medication usage in patients with AA, total all-cause health care costs did not significantly differ between the AA and AD cohorts ($10,705 vs $10,816; P = 0.712), and outpatient costs were higher in patients with AA ($6,297 vs $5,859; P = 0.014). Female patients with AA had significantly greater costs for both outpatient and outpatient pharmacy when compared with female patients with AD. Patients with AA were more likely to have a claim for long-term disability (0.6% vs 0.3%; P = 0.001) and higher long-term disability-associated indirect costs ($73 [SD = $1,442] vs $25 [SD = $774]; P = 0.004) compared with patients with AD. CONCLUSIONS: We found similar total health care costs in patients with AA and AD, despite a lower proportion of comorbidities and prescription use in patients with AA. Outpatient costs were also significantly higher overall in patients with AA. Although often dismissed as a cosmetic condition, AA, an autoimmune disease, has a similar level of medical expenditure as AD. DISCLOSURES: This study was funded by Eli Lilly and Company. Mr Fenske and Drs Ding, Morrow, and Smith are employed by Eli Lilly and Company. Drs Manjelievskaia, Moynihan, and Silver are employed by Merative. Drs Manjelievskaia, Moynihan, and Silver were employed by IBM Watson Health at the time of study completion. IBM Watson Health received funding from Eli Lilly and Company to conduct this study.

Prenatal Exposure to Glyphosate and Its Environmental Degradate, Aminomethylphosphonic Acid (AMPA), and Preterm Birth: A Nested Case-Control Study in the PROTECT Cohort (Puerto Rico).

BACKGROUND: Glyphosate (GLY) is the most heavily used herbicide in the world. Despite nearly ubiquitous exposure, few studies have examined prenatal GLY exposure and potentially adverse pregnancy outcomes. Preterm birth (PTB) is a risk factor for neonatal mortality and adverse health effects in childhood. OBJECTIVES: We examined prenatal exposure to GLY and a highly persistent environmental degradate of GLY, aminomethylphosphonic acid (AMPA), and odds of PTB in a nested case-control study within the ongoing Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) pregnancy cohort in northern Puerto Rico. METHODS: GLY and AMPA in urine samples collected at 18±2 (Visit 1) and 26±2 (Visit 3) wk gestation (53 cases/194 randomly selected controls) were measured using gas chromatography tandem mass spectrometry. Multivariable logistic regression was used to estimate associations with PTB (delivery <37wk completed gestation). RESULTS: Detection rates in controls were 77.4% and 77.5% for GLY and 52.8% and 47.7% for AMPA, and geometric means (geometric standard deviations) were 0.44 (2.50) and 0.41 (2.56) µg/L for GLY and 0.25 (3.06) and 0.20 (2.87) µg/L for AMPA, for Visits 1 and 3, respectively. PTB was significantly associated with specific gravity-corrected urinary GLY and AMPA at Visit 3, whereas associations with levels at Visit 1 and the Visits 1-3 average were largely null or inconsistent. Adjusted odds ratios (ORs) for an interquartile range increase in exposure at Visit 3 were 1.35 (95% CI: 0.99, 1.83) and 1.67 (95% CI: 1.26, 2.20) for GLY and AMPA, respectively. ORs for Visit 1 and the visit average were closer to the null. DISCUSSION: Urine GLY and AMPA levels in samples collected near the 26th week of pregnancy were associated with increased odds of PTB in this modestly sized nested case-control study. Given the widespread use of GLY, multiple potential sources of AMPA, and AMPA's persistence in the environment, as well as the potential for long-term adverse health effects in preterm infants, further investigation in other populations is warranted. https://doi.org/10.1289/EHP7295.

Distribution and predictors of 20 toxic and essential metals in the umbilical cord blood of Chinese newborns.

Early-life exposure to heavy metals and/or trace metal imbalances can have negative developmental effects. Here we sought to characterize exposure profiles for 20 heavy metals and trace elements in umbilical cord blood plasma and identify demographic predictors of exposure. Twenty metals were measured in cord plasma from 357 Chinese infants using ICP-MS. Relationships between demographic variables and metals were analyzed using generalized linear models and logistic regression. Ten metals (antimony [Sb], cobalt [Co], cesium [Cs], copper [Cu], lead [Pb], molybdenum [Mo], rubidium [Rb], selenium [Se], strontium [Sr], titanium [Ti], zinc [Zn]) were detected in all samples. Season of birth was the strongest predictor of metals in cord blood across analyses. Infants born in the spring had 0.1-0.2 µg L-1 higher logAs and logCo in their cord blood (ß [95%CI] = 0.22 [0.01,0.42], p = 0.04; 0.11 [0.01,0.22], p = 0.04), while infants born in the summer had higher Sb, logB, logHg, and logZn (ß [95%CI] = 0.74 [0.24,1.24], p = 0.004; 0.11 [0.00,0.21], p = 0.04; 0.29 [0.08,0.49], p = 0.007; 0.18 [0.06,0.31], p = 0.005), compared to those born in fall/winter. Prenatal heavy metal exposure and/or trace metal deficiencies are global concerns because of increasing awareness of downstream developmental effects.

Prenatal organophosphate insecticide exposure and infant sensory function.

BACKGROUND: Occupational studies suggest that exposure to organophosphate insecticides (OPs) can lead to vision or hearing loss. Yet the effects of early-life exposure on visual and auditory function are unknown. Here we examined associations between prenatal OP exposure and grating visual acuity (VA) and auditory brainstem response (ABR) during infancy. METHODS: 30 OPs were measured in umbilical cord blood using gas chromatography tandem mass spectrometry in a cohort of Chinese infants. Grating visual acuity (VA) (n = 179-200) and auditory brainstem response (ABR) (n = 139-183) were assessed at 6 weeks, 9 months, and 18 months. Outcomes included VA score, ABR wave V latency and central conduction time, and head circumference (HC). Associations between sensory outcomes during infancy and cord OPs were examined using linear mixed models. RESULTS: Prenatal chlorpyrifos exposure was associated with lower 9-month grating VA scores; scores were 0.64 (95% CI: -1.22, -0.06) points lower for exposed versus unexposed infants (p = 0.03). The OPs examined were not associated with infant ABR latencies, but chlorpyrifos and phorate were both significantly inversely associated with HC at 9 months; HCs were 0.41 (95% CI: 0.75, 0.6) cm and 0.44 (95% CI: 0.88, 0.1) cm smaller for chlorpyrifos (p = 0.02) and phorate (p = 0.04), respectively. CONCLUSIONS: We found deficits in grating VA and HC in 9-month-old infants with prenatal exposure to chlorpyrifos. The clinical significance of these small but statistically significant deficits is unclear. However, the disruption of visual or auditory pathway maturation in infancy could potentially negatively affect downstream cognitive development.

Prenatal naled and chlorpyrifos exposure is associated with deficits in infant motor function in a cohort of Chinese infants.

BACKGROUND: Organophosphate insecticides (OPs) are used worldwide, yet despite nearly ubiquitous exposure in the general population, few have been studied outside the laboratory. Fetal brains undergo rapid growth and development, leaving them susceptible to long-term effects of neurotoxic OPs. The objective here was to investigate the extent to which prenatal exposure to OPs affects infant motor development. METHODS: 30 OPs were measured in umbilical cord blood using gas chromatography tandem mass spectrometry in a cohort of Chinese infants. Motor function was assessed at 6-weeks and 9-months using Peabody Developmental Motor Scales 2nd edition (PDMS-2) (n=199). Outcomes included subtest scores: reflexes, stationary, locomotion, grasping, visual-motor integration (V-M), composite scores: gross (GM), fine (FM), total motor (TM), and standardized motor quotients: gross (GMQ), fine (FMQ), total motor (TMQ). RESULTS: Naled, methamidophos, trichlorfon, chlorpyrifos, and phorate were detected in ≥10% of samples. Prenatal naled and chlorpyrifos were associated with decreased 9-month motor function. Scores were 0.55, 0.85, and 0.90 points lower per 1ng/mL increase in log-naled, for V-M (p=0.04), FM (p=0.04), and FMQ (p=0.08), respectively. For chlorpyrifos, scores were 0.50, 1.98, 0.80, 1.91, 3.49, 2.71, 6.29, 2.56, 2.04, and 2.59 points lower for exposed versus unexposed infants, for reflexes (p=0.04), locomotion (p=0.02), grasping (p=0.05), V-M (p<0.001), GM (p=0.007), FM (p=0.002), TM (p<0.001), GMQ (p=0.01), FMQ (p=0.07), and TMQ (p=0.008), respectively. Girls appeared to be more sensitive to the negative effects of OPs on 9-month motor function than boys. CONCLUSIONS: We found deficits in 9-month motor function in infants with prenatal exposure to naled and chlorpyrifos. Naled is being aerially sprayed to combat mosquitoes carrying Zika virus, yet this is the first non-occupational human study of its health effects. Delays in early-motor skill acquisition may be detrimental for downstream development and cognition.

Prenatal exposure to multiple pesticides is associated with auditory brainstem response at 9months in a cohort study of Chinese infants.

BACKGROUND: Pesticides are associated with poorer neurodevelopmental outcomes, but little is known about the effects on sensory functioning. METHODS: Auditory brainstem response (ABR) and pesticide data were available for 27 healthy, full-term 9-month-old infants participating in a larger study of early iron deficiency and neurodevelopment. Cord blood was analyzed by gas chromatography-mass spectrometry for levels of 20 common pesticides. The ABR forward-masking condition consisted of a click stimulus (masker) delivered via ear canal transducers followed by an identical stimulus delayed by 8, 16, or 64 milliseconds (ms). ABR peak latencies were evaluated as a function of masker-stimulus time interval. Shorter wave latencies reflect faster neural conduction, more mature auditory pathways, and greater degree of myelination. Linear regression models were used to evaluate associations between total number of pesticides detected and ABR outcomes. We considered an additive or synergistic effect of poor iron status by stratifying our analysis by newborn ferritin (based on median split). RESULTS: Infants in the sample were highly exposed to pesticides; a mean of 4.1 pesticides were detected (range 0-9). ABR Wave V latency and central conduction time (CCT) were associated with the number of pesticides detected in cord blood for the 64ms and non-masker conditions. A similar pattern seen for CCT from the 8ms and 16ms conditions, although statistical significance was not reached. Increased pesticide exposure was associated with longer latency. The relation between number of pesticides detected in cord blood and CCT depended on the infant's cord blood ferritin level. Specifically, the relation was present in the lower cord blood ferritin group but not the higher cord blood ferritin group. CONCLUSIONS: ABR processing was slower in infants with greater prenatal pesticide exposure, indicating impaired neuromaturation. Infants with lower cord blood ferritin appeared to be more sensitive to the effects of prenatal pesticide exposure on ABR latency delay, suggesting an additive or multiplicative effect.

Distribution and Predictors of Pesticides in the Umbilical Cord Blood of Chinese Newborns.

Rates of pesticide use in Chinese agriculture are five times greater than the global average, leading to high exposure via the diet. Many are neurotoxic, making prenatal pesticide exposure a concern. Previous studies of prenatal exposure in China focused almost entirely on organochlorines. Here the study goals were to characterize the exposure of Chinese newborns to all classes of pesticides and identify predictors of those exposures. Eighty-four pesticides and 12 metabolites were measured in the umbilical cord plasma of 336 infants. Composite variables were created for totals detected overall and by class. Individual pesticides were analyzed as dichotomous or continuous, based on detection rates. Relationships between demographic characteristics and pesticides were evaluated using generalized linear regression. Seventy-five pesticides were detected. The mean number of detects per sample was 15.3. Increased pesticide detects were found in the cord blood of infants born in the summer (ß = 2.2, p = 0.01), particularly in July (ß = 4.0, p = 0.03). Similar trends were observed for individual insecticide classes. Thus, a summer birth was the strongest predictor of pesticide evidence in cord blood. Associations were more striking for overall pesticide exposure than for individual pesticides, highlighting the importance of considering exposure to mixtures of pesticides, rather than individual agents or classes.

Urinary bisphenol A and type-2 diabetes in U.S. adults: data from NHANES 2003-2008.

OBJECTIVE: Bisphenol A (BPA) is found in plastics and other consumer products; exposure may lead to insulin resistance and development of type-2 diabetes mellitus (T2DM) through over-activation of pancreatic ß-cells. Previous studies using data from the National Health and Nutrition Examination Survey (NHANES) showed an inconsistent association between prevalence of self-reported T2DM and urinary BPA. We used a different diagnosis method of T2DM (hemoglobin A1c (HbA1c)) with a larger subset of NHANES. METHODS AND FINDINGS: We analyzed data from 4,389 adult participants who were part of a sub-study of environmental phenol measurements in urine from three NHANES cycles from 2003 to 2008. T2DM was defined as having a HbA1c ≥ 6.5% or use of diabetes medication. The weighted prevalence of T2DM was 9.2%. Analysis of the total sample revealed that a two-fold increase in urinary BPA was associated with an odds ratio (OR) of 1.08 of T2DM (95% confidence interval (CI), 1.02 to 1.16), after controlling for potential confounders. However, when we examined each NHANES cycle individually, we only found a statistically significant association in the 2003/04 cycle (n = 1,364, OR = 1.23 (95% CI, 1.07 to 1.42) for each doubling in urinary BPA). We found no association in either the NHANES cycle from 2005/06 (n = 1,363, OR = 1.05 (95% CI, 0.94 to 1.18)); or 2007/08 (n = 1,662, OR = 1.06 (95% CI, 0.91 to 1.23)). Similar patterns of associations between BPA and continuous HbA1c were also observed. CONCLUSIONS: Although higher urinary BPA was associated with elevated HbA1c and T2DM in the pooled analysis, it was driven by data from only one NHANES cycle. Additional studies, especially of a longitudinal design with repeated BPA measurements, are needed to further elucidate the association between BPA and T2DM.

Structure and functional analysis of RifR, the type II thioesterase from the rifamycin biosynthetic pathway.

Two thioesterases are commonly found in natural product biosynthetic clusters, a type I thioesterase that is responsible for removing the final product from the biosynthetic complex and a type II thioesterase that is believed to perform housekeeping functions such as removing aberrant units from carrier domains. We present the crystal structure and the kinetic analysis of RifR, a type II thioesterase from the hybrid nonribosomal peptide synthetases/polyketide synthase rifamycin biosynthetic cluster of Amycolatopsis mediterranei. Steady-state kinetics show that RifR has a preference for the hydrolysis of acyl units from the phosphopantetheinyl arm of the acyl carrier domain over the hydrolysis of acyl units from the phosphopantetheinyl arm of acyl-CoAs as well as a modest preference for the decarboxylated substrate mimics acetyl-CoA and propionyl-CoA over malonyl-CoA and methylmalonyl-CoA. Multiple RifR conformations and structural similarities to other thioesterases suggest that movement of a helical lid controls access of substrates to the active site of RifR.