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Organophosphate (OP) insecticides are some of the most abundantly used insecticides, and prenatal exposures have been linked to adverse maternal and child health outcomes. Anogenital distance (AGD) has emerged as an early marker of androgen activity, and later reproductive outcomes, that is sensitive to alteration by environmental chemicals. Here, we examined associations between prenatal exposure to chlorpyrifos, an OP insecticide, with AGD. Pregnant farmworkers were enrolled in the Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE; N = 104) between 2017 and 2019 in Northern Thailand. Concentrations of 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of chlorpyrifos, were measured in composited urine samples obtained from each trimester of pregnancy. AGD was measured at 12 months of age. Sex-specific adjusted linear regression models were used to examine associations between average and trimester-specific TCPy levels and AGD. In adjusted models for females and males, increasing TCPy was consistently associated with a modest, non-significant reduction in AGD. Across both strata of sex, associations were greatest in magnitude for trimester 3 (females: ß = -2.17, 95 % confidence interval (CI) = -4.99, 0.66; males: ß = -3.02, 95 % CI = -6.39, 0.35). In the SAWASDEE study, prenatal chlorpyrifos exposure was not strongly associated with AGD at 12 months of age.
Asunto(s)
Cloropirifos , Insecticidas , Masculino , Embarazo , Niño , Humanos , Femenino , Cloropirifos/orina , Insecticidas/orina , Tailandia , Agricultores , Exposición a Riesgos Ambientales , Exposición MaternaRESUMEN
INTRODUCTION: Organophosphate (OP) insecticides, including chlorpyrifos, have been linked with numerous harmful health effects on maternal and child health. Limited data are available on the biological mechanisms and endogenous pathways underlying the toxicity of chlorpyrifos exposures on pregnancy and birth outcomes. In this study, we measured a urinary chlorpyrifos metabolite and used high-resolution metabolomics (HRM) to identify biological perturbations associated with chlorpyrifos exposure among pregnant women in Thailand, who are disparately exposed to high levels of OP insecticides. METHODS: This study included 50 participants from the Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE). We used liquid chromatography-high resolution mass spectrometry to conduct metabolic profiling on first trimester serum samples collected from participants to evaluate metabolic perturbations in relation to chlorpyrifos exposures. We measured 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of chlorpyrifos and chlorpyrifos-methyl, in first trimester urine samples to assess the levels of exposures. Following an untargeted metabolome-wide association study workflow, we used generalized linear models, pathway enrichment analyses, and chemical annotation to identify significant metabolites and pathways associated with urinary TCPy levels. RESULTS: In the 50 SAWASDEE participants, the median urinary TCPy level was 4.36 µg TCPy/g creatinine. In total, 691 unique metabolic features were found significantly associated with TCPy levels (p < 0.05) after controlling for confounding factors. Pathway analysis of metabolic features associated with TCPy indicated perturbations in 24 metabolic pathways, most closely linked to the production of reactive oxygen species and cellular damage. These pathways include tryptophan metabolism, fatty acid oxidation and peroxisome metabolism, cytochromes P450 metabolism, glutathione metabolism, and vitamin B3 metabolism. We confirmed the chemical identities of 25 metabolites associated with TCPy levels, including glutathione, cystine, arachidic acid, itaconate, and nicotinamide adenine dinucleotide. DISCUSSION: The metabolic perturbations associated with TCPy levels were related to oxidative stress, cellular damage and repair, and systemic inflammation, which could ultimately contribute to health outcomes, including neurodevelopmental deficits in the child. These findings support the future development of sensitive biomarkers to investigate the metabolic underpinnings related to pesticide exposure during pregnancy and to understand its link to adverse outcomes in children.
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Cloropirifos , Insecticidas , Plaguicidas , Biomarcadores/orina , Niño , Creatinina , Cistina/metabolismo , Citocromos/metabolismo , Agricultores , Ácidos Grasos , Femenino , Glutatión/metabolismo , Humanos , Insecticidas/toxicidad , Metaboloma , NAD/metabolismo , Niacinamida , Compuestos Organofosforados/toxicidad , Plaguicidas/orina , Embarazo , Primer Trimestre del Embarazo , Especies Reactivas de Oxígeno , Tailandia , Triptófano/metabolismoRESUMEN
BACKGROUND: Prenatal exposure to pesticides has been linked to adverse neurodevelopmental outcomes. Gaps exist in the current literature about the timing and magnitude of exposures that result in these adverse outcomes. OBJECTIVE: The Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE) cohort was established to investigate the impact of prenatal exposure to pesticides on early indicators of cognitive and motor skills, inhibitory control, emotion regulation, and memory that have been found to be important in the development of subsequent neurobehavioral and neurodevelopmental diseases. The overarching goal is to find earlier predictors of potential adverse neurologic outcomes in order to enable earlier interventions that could result in better outcome prognoses. METHODS: Recruitment of this prospective, longitudinal birth cohort began in July 2017 and was completed in June 2019 in Chom Thong and Fang, 2 farming districts in Chiang Mai Province in northern Thailand. Follow-up of the study participants is ongoing. During pregnancy, 7 questionnaires were administered. Time-resolved biospecimen samples were collected monthly (for urine) and during each trimester (for blood) during antenatal care visits. Medical records were abstracted. Infants were administered the NICU Network Neurobehavioral Scale (NNNS) test at 1 month of age. A total of 322 mother-child pairs completed the NNNS test. All children will be followed until 3 years of age and undergo a series of neurodevelopmental tests. We will complete several additional exposure related analyses. RESULTS: A total of 1298 women were screened, and of those, 394 (30.35%) women were enrolled. The mean gestational age at enrollment was 9.9 weeks (SD 2.6). Differences in literacy were observed between Chom Thong and Fang participants. In Fang, about 54 of 105 (51.4%) participants reported being able to read in Thai compared to about 206 of 217 (94.9%) participants in Chom Thong. The percentages were comparable for reporting to be able to write in Thai. CONCLUSIONS: This longitudinal birth cohort study will inform risk assessment standards for pregnant women in Thailand and other countries. Building awareness of how insecticide exposure during specific windows of pregnancy affects the neurodevelopmental trajectories of children in developing countries is a specific need recognized by the World Health Organization. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31696.
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Introduction: Organophosphate (OP) insecticides are among the most abundantly used insecticides worldwide. Thailand ranked third among 15 Asian countries in its use of pesticides per unit hectare and fourth in annual pesticide use. More than 40% of Thai women of childbearing age work on farms where pesticides are applied. Thus, the potential for pregnant women and their fetuses to be exposed to pesticides is significant. This study investigated the relationship between early, mid, and late pregnancy maternal urine concentrations of OP metabolites and infant neural integrity at 5 weeks of age. Method: We enrolled women employed on farms from two antenatal clinics in the Chiang Mai province of northern Thailand. We collected urine samples monthly during pregnancy, composited them by early, mid and late pregnancy and analyzed the composited samples for dialkylphosphate (DAP) metabolites of OP insecticides. At 5 weeks after birth, nurses certified in use of the NICU Network Neurobehavioral Scale (NNNS) completed the evaluation of 320 healthy infants. We employed generalized linear regression, logistic and Poisson models to determine the association between NNNS outcomes and DAP concentrations. All analyses were adjusted for confounders and included creatinine as an independent variable. Results: We did not observe trimester specific associations between DAP concentrations and NNNS outcomes. Instead, we observed statistically significant inverse associations between NNNS arousal (ß = -0.10; CI: -0.17, -0.002; p = 0.0091) and excitability [0.79 (0.68, 0.92; p = 0.0026)] among participants with higher average prenatal DAP concentrations across pregnancy. We identified 3 NNNS profiles by latent profile analysis. Higher prenatal maternal DAP concentrations were associated with higher odds of being classified in a profile indicative of greater self-regulation and attention, but arousal and excitability scores below the 50th percentile relative to US normative samples [OR = 1.47 (CI: 1.05, 2.06; p = 0.03)]. Similar findings are also observed among infants with prenatal exposure to substances of abuse (e.g., methamphetamine). Discussion: Overall, the associations between prenatal DAP concentrations and NNNS summary scores were not significant. Further evaluations are warranted to determine the implications of low arousal and excitability for neurodevelopmental outcomes of attention and memory and whether these results are transitory or imply inadequate responsivity to stimulation among children as they develop.
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BACKGROUND: Measurements of urinary dialkyl phosphate (DAP) metabolites are often used to characterize exposures to organophosphate (OP) insecticides; however, some challenges to using urinary DAP metabolites as an exposure measure exist. OP insecticides have short biological half-lives with measurement in a single urine sample typically only reflecting recent exposure within the last few days. Because of the field staff and participant burden of longitudinal sample collection and the high cost of multiple measurements, typically only one or two urine samples have been used to evaluate OP insecticide exposure during pregnancy, which is unlikely to capture an accurate picture of prenatal exposure. METHODS: We recruited pregnant farmworker women in Chom Thong and Fang, two districts of Chiang Mai province in northern Thailand (N = 330) into the Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE) from 2017 to 2019. We collected up to 6 serial urine samples per participant during gestation and composited the samples to represent early, mid, and late pregnancy. We measured concentrations of urinary DAP metabolites in the composited urine samples and evaluated the within- and between-participant variability of these levels. We also investigated predictors of OP insecticide exposure. RESULTS: DAP metabolite concentrations in serial composite samples were weakly to moderately correlated. Spearman correlations indicated that composite urine samples were more highly correlated in Fang participants than in Chom Thong participants. The within-person variances (0.064-0.65) exceeded the between-person variances for DETP, DEP, ∑DEAP, DMP, DMTP, ∑DMAP, ∑DAP. The intraclass correlations (ICCs) for the volume-based individual metabolite levels (ng/mL) ranged from 0.10 to 0.66. For ∑DEAP, ∑DMAP, and ∑DAP the ICCs were, 0.47, 0.17, 0.45 respectively. We observed significant differences between participants from Fang compared to those from Chom Thong both in demographic and exposure characteristics. Spearman correlations of composite samples from Fang participants ranged from 0.55 to 0.66 for the ∑DEAP metabolite concentrations in Fang indicating moderate correlation between pregnancy periods. The ICCs were higher for samples from Fang participants, which drove the overall ICCs. CONCLUSIONS: Collecting multiple (â¼6) urine samples during pregnancy rather than just 1 or 2 improved our ability to accurately assess exposure during the prenatal period. By compositing the samples, we were able to still obtain trimester-specific information on exposure while keeping the analytic costs and laboratory burden low. This analysis also helped to inform how to best conduct future analyses within the SAWASDEE study. We observed two different exposure profiles in participants in which the concentrations and variability in data were highly linked to the residential location of the participants.