Bibliography Tag: birth defects

Eunha et al., 2022

Eunha Kim, Donggi Paik, Ricardo N. Ramirez, Delaney G. Biggs, Youngjun Park, Ho-Keun Kwon, Gloria B. Choi, Jun R. Huh.; “Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4+ T cells;” Immunity, 2022, 55(1), 145-158; 10.1016/j.immuni.2021.11.005.


Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4+ T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders. FULL TEXT


Rappazzo et al., 2018

Rappazzo, K. M., Warren, J. L., Davalos, A. D., Meyer, R. E., Sanders, A. P., Brownstein, N. C., & Luben, T. J.; “Maternal residential exposure to specific agricultural pesticide active ingredients and birth defects in a 2003-2005 North Carolina birth cohort;” Birth Defects Research, 2018; DOI: 10.1002/bdr2.1448.


BACKGROUND: Previously we observed elevated odds ratios (ORs) for total pesticide exposure and 10 birth defects: three congenital heart defects and structural defects affecting the gastrointestinal, genitourinary and musculoskeletal systems. This analysis examines association of those defects with exposure to seven commonly applied pesticide active ingredients.

METHODS: Cases were live-born singleton infants from the North Carolina Birth Defects Monitoring Program linked to birth records for 2003-2005; noncases served as controls (total n = 304,906). Pesticide active ingredient exposure was assigned using a previously constructed metric based on crops within 500 m of residence, dates of pregnancy, and likely chemical application dates for each pesticide-crop combination. ORs (95% CI) were estimated with logistic regression for categories of exposure compared to unexposed. Models were adjusted for maternal race/ethnicity, age at delivery, education, marital status, and smoking status.

RESULTS: Associations varied by birth defect and pesticide combinations. For example, hypospadias was positively associated with exposures to 2,4-D (OR50th to <90th percentile : 1.39 [1.18, 1.64]), mepiquat (OR50th to <90th percentile : 1.10 [0.90, 1.34]), paraquat (OR50th to <90th : 1.14 [0.93, 1.39]), and pendimethalin (OR50th to <90th : 1.21 [1.01, 1.44]), but not S-metolachlor (OR50th to <90th : 1.00 [0.81, 1.22]). Whereas atrial septal defects were positively associated with higher levels of exposure to glyphosate, cyhalothrin, S-metolachlor, mepiquat, and pendimethalin (ORs ranged from 1.22 to 1.35 for 50th to <90th exposures, and 1.72 to 2.09 for >90th exposures); associations with paraquat were null or inconsistent (OR 50th to <90th: 1.05 (0.87, 1.27).

CONCLUSION: Our results suggest differing patterns of association for birth defects with residential exposure to seven pesticide active ingredients in North Carolina.

Maurice et al., 2021

Maurice C, Dalvai M, Lambrot R, Deschênes A, Scott-Boyer M-P, McGraw S, Chan D, Côté N, Ziv-Gal A, Flaws JA, Droit A, Trasler J, Kimmins S, Bailey JL. “Early-Life Exposure to Environmental Contaminants Perturbs the Sperm Epigenome and Induces Negative Pregnancy Outcomes for Three Generations via the Paternal Lineage.” Epigenomes. 2021, 5(2):10; DOI:10.3390/epigenomes5020010


Due to the grasshopper effect, the Arctic food chain in Canada is contaminated with persistent organic pollutants (POPs) of industrial origin, including polychlorinated biphenyls and organochlorine pesticides. Exposure to POPs may be a contributor to the greater incidence of poor fetal growth, placental abnormalities, stillbirths, congenital defects and shortened lifespan in the Inuit population compared to non-Aboriginal Canadians. Although maternal exposure to POPs is well established to harm pregnancy outcomes, paternal transmission of the effects of POPs is a possibility that has not been well investigated. We used a rat model to test the hypothesis that exposure to POPs during gestation and suckling leads to developmental defects that are transmitted to subsequent generations via the male lineage. Indeed, developmental exposure to an environmentally relevant Arctic POPs mixture impaired sperm quality and pregnancy outcomes across two subsequent, unexposed generations and altered sperm DNA methylation, some of which are also observed for two additional generations. Genes corresponding to the altered sperm methylome correspond to health problems encountered in the Inuit population. These findings demonstrate that the paternal methylome is sensitive to the environment and that some perturbations persist for at least two subsequent generations. In conclusion, although many factors influence health, paternal exposure to contaminants plays a heretofore-underappreciated role with sperm DNA methylation contributing to the molecular underpinnings involved. FULL TEXT

Coullery et al., 2020

Coullery, R., Pacchioni, A. M., & Rosso, S. B.; “Exposure to glyphosate during pregnancy induces neurobehavioral alterations and downregulation of Wnt5a-CaMKII pathway;” Reproductive Toxicology, 2020, 96, 390-398; DOI: 10.1016/j.reprotox.2020.08.006.


Glyphosate-based formulations are the most popular herbicide used around the world. These herbicides are widely applied in agriculture to control weeds on genetically modified crops. Although there is much evidence showing that glyphosate-based herbicides induce toxic effect on reproductive and hepatic systems, and also cause oxidative damage on cells, studies from recent years revealed that the nervous system may represent a key target for their toxicity. In the present work, we evaluated the effect of glyphosate (without adjuvants) in neonate rats after gestational exposure. Particularly, we examined whether glyphosate during gestation affected the nervous system function at early development. Pregnant Wistar rats were treated with 24 or 35mg/kg of pure glyphosate every 48h and neurobehavioral studies were performed. Our results indicated that gestational exposure to glyphosate induced changes in reflexes development, motor activity and cognitive function, in a dose-dependent manner. To go further, we evaluated whether prenatal exposure to glyphosate affected the Ca(+2)-mediated Wnt non-canonical signaling pathway. Results indicated that embryos exposed to glyphosate showed an inhibition of Wnt5a-CaMKII signaling pathway, an essential cascade controlling the formation and integration of neural circuits. Taken together, these findings suggest that gestational exposure to glyphosate leads to a downregulation of Wnt/Ca(+2) pathway that could induce a developmental neurotoxicity evidenced by deficits at behavioral and cognitive levels in rat pups. FULL TEXT

Larsen et al., 2017

Larsen, A. E., Gaines, S. D., & Deschenes, O.; “Agricultural pesticide use and adverse birth outcomes in the San Joaquin Valley of California;” Nature Communications, 2017, 8(1), 302; DOI: 10.1038/s41467-017-00349-2.


Virtually all agricultural communities worldwide are exposed to agricultural pesticides. Yet, the health consequences of such exposure are poorly understood, and the scientific literature remains ambiguous. Using individual birth and demographic characteristics for over 500 000 birth observations between 1997-2011 in the agriculturally dominated San Joaquin Valley, California, we statistically investigate if residential agricultural pesticide exposure during gestation, by trimester, and by toxicity influences birth weight, gestational length, or birth abnormalities. Overall, our analysis indicates that agricultural pesticide exposure increases adverse birth outcomes by 5-9%, but only among the population exposed to very high quantities of pesticides (e.g., top 5th percentile, i.e., ~4200 kg applied over gestation). Thus, policies and interventions targeting the extreme right tail of the pesticide distribution near human habitation could largely eliminate the adverse birth outcomes associated with agricultural pesticide exposure documented in this study.The health consequences of exposure to pesticides are uncertain and subject to much debate. Here, the effect of exposure during pregnancy is investigated in an agriculturally dominated residential area, showing that an increase in adverse birth outcomes is observed with very high levels of pesticide exposure. FULL TEXT

Cattani et al., 2017

Cattani, D., Cesconetto, P. A., Tavares, M. K., Parisotto, E. B., De Oliveira, P. A., Rieg, C. E. H., Leite, M. C., Prediger, R. D. S., Wendt, N. C., Razzera, G., Filho, D. W., & Zamoner, A., “Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: Implication of glutamate excitotoxicity and oxidative stress,” Toxicology, 2017, 387, 67-80. DOI: 10.1016/j.tox.2017.06.001.


We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[(14)C]-glutamate uptake and increased (45)Ca(2+) influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive-like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-kappaB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring. FULL TEXT

Milesi et al., 2018

Milesi, Maria M, Lorenz, Virginia, Pacini, Guillermina, Repetti, Maria R, Demonte, Luisina D, Varayoud, Jorgelina, & Luque, Enrique H, “Perinatal exposure to a glyphosate-based herbicide impairs female reproductive outcomes and induces second-generation adverse effects in Wistar rats,” Archives of Toxicology, 2018, 92(8), 2629-2643. DOI: 10.1007/s00204-018-2236-6.


Glyphosate-based herbicides (GBHs) are the most globally used herbicides raising the risk of environmental exposition. Here, we investigated whether perinatal exposure to low doses of a GBH alters the female reproductive performance, and/or induced second-generation effects related to congenital anomalies or growth alterations. Pregnant rats (F0) received a GBH through food, in a dose of 2 mg (GBH-LD: GBH-low dose group) or 200 mg (GBH-HD: GBH-high dose group) of glyphosate/kg bw/day from gestational day (GD) 9 until weaning. Body weight gain and vaginal canal-opening of F1 females were recorded. Sexually mature F1 females were mated to evaluate their reproductive performance by assessing the pregnancy rate, and on GD19, the number of corpora lutea, the implantation sites (IS) and resorption sites. To analyze second-generation effects on F2 offspring, we analyzed the fetal morphology on GD19, and assessed the fetal length and weight, and the placental weight. GBH exposure neither altered the body weight gain of F1 females, nor vaginal opening onset. Although all GBH-exposed F1 rats became pregnant, a lower number of IS was detected. F2 offspring from both GBH groups showed delayed growth, evidenced by lower fetal weight and length, associated with a higher incidence of small for gestational age fetuses. In addition, higher placental weight and placental index were found in F2 offspring from GBH-HD dams. Surprisingly, structural congenital anomalies (conjoined fetuses and abnormally developed limbs) were detected in the F2 offspring from GBH-HD group. In conclusion, perinatal exposure to low doses of a GBH impaired female reproductive performance and induced fetal growth retardation and structural congenital anomalies in F2 offspring. FULL TEXT

Wigle et al., 2008

Donald T. Wigle , Tye E. Arbuckle , Michelle C. Turner , Annie Bérubé , Qiuying Yang , Shiliang Liu & Daniel Krewski, “Epidemiologic Evidence of Relationships Between Reproductive and Child Health Outcomes and Environmental Chemical Contaminants,” Journal of Toxicology and Environmental Health, Part B, 11, 2008, DOI: 10.1080/10937400801921320


This review summarizes the level of epidemiologic evidence for relationships between prenatal and/or early life exposure to environmental chemical contaminants and fetal, child, and adult health. Discussion focuses on fetal loss, intrauterine growth restriction, preterm birth, birth defects, respiratory and other childhood diseases, neuropsychological deficits, premature or delayed sexual maturation, and certain adult cancers linked to fetal or childhood exposures. Environmental exposures considered here include chemical toxicants in air, water, soil/house dust and foods (including human breast milk), and consumer products. Reports reviewed here included original epidemiologic studies (with at least basic descriptions of methods and results), literature reviews, expert group reports, meta-analyses, and pooled analyses. Levels of evidence for causal relationships were categorized as sufficient, limited, or inadequate according to predefined criteria. There was sufficient epidemiological evidence for causal relationships between several adverse pregnancy or child health outcomes and prenatal or childhood exposure to environmental chemical contaminants. These included prenatal high-level methylmercury (CH3Hg) exposure (delayed developmental milestones and cognitive, motor, auditory, and visual deficits), high-level prenatal exposure to polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and related toxicants (neonatal tooth abnormalities, cognitive and motor deficits), maternal active smoking (delayed conception, preterm birth, fetal growth deficit [FGD] and sudden infant death syndrome [SIDS]) and prenatal environmental tobacco smoke (ETS) exposure (preterm birth), low-level childhood lead exposure (cognitive deficits and renal tubular damage), high-level childhood CH3Hg exposure (visual deficits), high-level childhood exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (chloracne), childhood ETS exposure (SIDS, new-onset asthma, increased asthma severity, lung and middle ear infections, and adult breast and lung cancer), childhood exposure to biomass smoke (lung infections), and childhood exposure to outdoor air pollutants (increased asthma severity). Evidence for some proven relationships came from investigation of relatively small numbers of children with high-dose prenatal or early childhood exposures, e.g., CH3Hg poisoning episodes in Japan and Iraq. In contrast, consensus on a causal relationship between incident asthma and ETS exposure came only recently after many studies and prolonged debate. There were many relationships supported by limited epidemiologic evidence, ranging from several studies with fairly consistent findings and evidence of dose-response relationships to those where 20 or more studies provided inconsistent or otherwise less than convincing evidence of an association. The latter included childhood cancer and parental or childhood exposures to pesticides. In most cases, relationships supported by inadequate epidemiologic evidence reflect scarcity of evidence as opposed to strong evidence of no effect. This summary points to three main needs: (1) Where relationships between child health and environmental exposures are supported by sufficient evidence of causal relationships, there is a need for (a) policies and programs to minimize population exposures and (b) population-based biomonitoring to track exposure levels, i.e., through ongoing or periodic surveys with measurements of contaminant levels in blood, urine and other samples. (2) For relationships supported by limited evidence, there is a need for targeted research and policy options ranging from ongoing evaluation of evidence to proactive actions. (3) There is a great need for population-based, multidisciplinary and collaborative research on the many relationships supported by inadequate evidence, as these represent major knowledge gaps. Expert groups faced with evaluating epidemiologic evidence of potential causal relationships repeatedly encounter problems in summarizing the available data. A major driver for undertaking such summaries is the need to compensate for the limited sample sizes of individual epidemiologic studies. Sample size limitations are major obstacles to exploration of prenatal, paternal, and childhood exposures during specific time windows, exposure intensity, exposure–exposure or exposure–gene interactions, and relatively rare health outcomes such as childhood cancer. Such research needs call for investments in research infrastructure, including human resources and methods development (standardized protocols, biomarker research, validated exposure metrics, reference analytic laboratories). These are needed to generate research findings that can be compared and subjected to pooled analyses aimed at knowledge synthesis.

Bradman et al., 2013

Bradman, Asa; Kogut, Katherine; Eisen, Ellen A; Jewell, Nicholas P; Quiros-Alcala, Lesliam; Castorina, Rosemary; Chevrier, Jonathan; Holland, Nina T;  Barr, Dana Boyd; Kavanagh-Baird, Geri; Eskenazi, Brenda, “Variability of organophosphorous pesticide metabolite levels in spot and 24-hr urine samples collected from young children during 1 week,” Environmental Health Perspectives, 2013, 121:118-124. DOI:10.1289/ehp.1104808.


BACKGROUND: Dialkyl phosphate (DAP) metabolites in spot urine samples are frequently used to characterize children’s exposures to organophosphorous (OP) pesticides. However, variable exposure and short biological half-lives of OP pesticides could result in highly variable measurements, leading to exposure misclassification.

OBJECTIVE: We examined within- and between-child variability in DAP metabolites in urine samples collected during 1 week.

METHODS: We collected spot urine samples over 7 consecutive days from 25 children (3-6 years of age). On two of the days, we collected 24-hr voids. We assessed the reproducibility of urinary DAP metabolite concentrations and evaluated the sensitivity and specificity of spot urine samples as predictors of high (top 20%) or elevated (top 40%) weekly average DAP metabolite concentrations.

RESULTS: Within-child variance exceeded between-child variance by a factor of two to eight, depending on metabolite grouping. Although total DAP concentrations in single spot urine samples were moderately to strongly associated with concentrations in same-day 24-hr samples (r approximately 0.6-0.8, p < 0.01), concentrations in spot samples collected > 1 day apart and in 24-hr samples collected 3 days apart were weakly correlated (r approximately -0.21 to 0.38). Single spot samples predicted high (top 20%) and elevated (top 40%) full-week average total DAP excretion with only moderate sensitivity ( approximately 0.52 and approximately 0.67, respectively) but relatively high specificity ( approximately 0.88 and approximately 0.78, respectively).

CONCLUSIONS: The high variability we observed in children’s DAP metabolite concentrations suggests that single-day urine samples provide only a brief snapshot of exposure. Sensitivity analyses suggest that classification of cumulative OP exposure based on spot samples is prone to type 2 classification errors.  FULL TEXT

Bradman et al., 2003

Bradman A, Barr DB, Claus Henn BG, Drumheller T, Curry C, Eskenazi B, “Measurement of pesticides and other toxicants in amniotic fluid as a potential biomarker of prenatal exposure: a validation study,” Environmental Health Perspectives, 2003, 111:1779-1782. DOI:10.1289/ehp.6259.


Prenatal pesticide exposures may adversely affect children’s health. However, exposure and health research is hampered by the lack of reliable fetal exposure data. No studies have been published that report measurements of commonly used nonpersistent pesticides in human amniotic fluid, although recent studies of pesticides in urine from pregnant women and in meconium indicate that fetuses are exposed to these chemicals. Amniotic fluid collected during amniocentesis is the only medium available to characterize direct fetal exposures early in pregnancy (approximately 18 weeks of gestation). As a first step in validating this exposure biomarker, we collected 100 amniotic fluid samples slated for disposal and evaluated analytical methods to measure organophosphate and carbamate pesticides and metabolites, synthetic pyrethroid metabolites, herbicides, and chlorinated phenolic compounds. The following six phenols were detected (detection frequency): 1- and 2-naphthol (70%), 2,5-dichlorophenol (55%), carbofuranphenol (5%), ortho-phenylphenol (30%), and pentachlorophenol (15%), with geometric mean concentrations of 0.72, 0.39, 0.12, 0.13, and 0.23 microg/L, respectively, for positive values. The organophosphate metabolites diethylphosphate and dimethylphosphate were detected in two (10%) samples, and dimethylthiophosphate was detected in one (5%) sample, with geometric mean concentrations of 0.31, 0.32, and 0.43 microg/L, respectively, for positive values. These levels are low compared with levels reported in urine, blood, and meconium in other studies, but indicate direct exposures to the young fetus, possibly during critical periods of development. Results of this pilot study suggest that amniotic fluid offers a unique opportunity to investigate fetal exposures and health risks.  FULL TEXT