Maternal DDT Research Articles

Prenatal exposure to insecticides and child weight trajectories in a South African birth cohort

Background: DDT or pyrethroid insecticides are sprayed inside dwellings as part of global malaria vector control programs, resulting in high levels of exposure to millions of people, including pregnant women. These chemicals are endocrine disruptors and may affect child growth. Study Design: The Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) is a birth cohort study based in Limpopo, South Africa (n=752). Maternal peripartum concentrations of DDT and its breakdown product DDE were measured in serum and pyrethroid metabolites were measured in urine. Child weight was measured at birth and at 1, 2, 3.5 and 5-year follow-up visits; weight measurements were also abstracted from medical records. Methods: We modelled child weight trajectories using SuperImposition, Translation and Rotation (SITAR) to estimate child-specific weight over time and age at peak weight velocity (APWV). We then estimated associations between insecticides and SITAR parameters using multivariable linear regression. We also investigated whether child sex and maternal energy intake sufficiency during pregnancy modified these associations. Results: Maternal p,p’-DDT was associated with greater weight among girls (β=14g per 10-fold increase; 95%CI=0, 28) and children of mothers with sufficient energy intake (β=18g per 10-fold increase; 95%CI=1, 35). We also found that pyrethroids may be associated with lower weight and earlier APWV among boys, particularly for cis-DBCA, which is specific to deltamethrin (βweight= -24g per 10-fold increase; 95%CI=-52, 4; βAPWV=-2.6 days per 10-fold increase; 95% CI: -5.3, 0.1). Conclusions: Maternal DDT and pyrethroid exposure may be associated with child growth through age 5. Positive associations between p,p’-DDT and weight among girls are consistent with its estrogenic properties, and inverse associations between pyrethroids and weight and APWV among boys may be related to their androgenic properties. These findings, as well as that of effect modification by maternal energy intake, support our previous research in this population.

Abstract A03: Preconception paternal DDT exposure and programming of metabolic dysfunction and breast cancer in offspring

Abstract The pesticide dichlorodiphenyltrichloroethane or DDT was widely used in agriculture or to combat insect-borne diseases until the 1970s in the United States and the 1980s in Europe. It continues to be used in developing countries to combat malaria or illegally to protect crops. Because of its prolonged half-life, DDT is a persistent environmental pollutant that still can detected in the American population, particularly in minorities and recent immigrants. Epidemiologic studies have shown that early-life (in utero and early childhood) exposure to DDT is associated with a four-fold increase in breast cancer risk in women, and these findings are supported by animal studies. While maternal DDT exposure in pregnancy has been linked to breast cancer in offspring, the effects of paternal DDT exposure on their progeny’s breast cancer development have not been investigated. Environmental exposures can induce epigenetic changes in paternal sperm and affect the risk of disease in their offspring. Here, we evaluated the effects of preconception exposure to DDT on the male sperm epigenome and programming of offspring’s susceptibility to breast cancer, using a mouse model. Male mice were exposed to DDT (1.7mg/kg body weight) by oral gavage in the preconception window. DDT and control-vehicle (CO) males were then used for sperm collection or housed with female mice, with free access to a standard chow diet, for three days. Pregnancy onset was assessed by the presence of a vaginal plug. The weight and number of pups per litter were determined two days after birth. Pups were weaned at 21 days of age and fed a standard chow diet for the extent of the study. Offspring were weighed weekly and used to study metabolic parameters. Mammary tumors were induced by administration of 15mg of medroxyprogesterone to six-week-old female offspring, followed by oral administration of 1mg 7,12-dimethylbenz[a]anthracene once a week for 3 weeks. RNA extracted from sperm CO and DDT males was used for small RNA-seq analysis. Preconception exposure to DDT altered small noncoding RNAs (e.g., miRNAs and tRNAs) in paternal sperm. In line with that, offspring of DDT-exposed fathers had a significant decrease in birth and weaning weights compared to controls. Further, DDT offspring showed metabolic dysfunction. Compared to CO, female offspring of DDT fathers had significantly accelerated breast tumor growth and a nonsignificant increase in mammary tumor incidence and shorter tumor latency. These tumor phenotypes were linked to mammary tissue inhibition of AMPK, a central metabolic sensor, and increased mTOR activity. In conclusion, our findings support a role for DDT exposure from the paternal lineage in metabolic dysfunction and increased breast cancer development in the offspring. Defining the mechanism by which paternal exposures to EDC such as DDT can promote breast cancer development in offspring is critical to identifying early detection/preventive approaches or treatments for this malignancy in a subset of women. Citation Format: Raquel Santana da Cruz, Hong Cao, Camile Fontelles, Apsra Nasir, Volkan Tekam, M. Idalia Cruz, Lu Jin, Sonia de Assis. Preconception paternal DDT exposure and programming of metabolic dysfunction and breast cancer in offspring [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A03.

Association between maternal exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) and risk of obesity in middle age.

Background:Obesity is a malnourishment epidemic worldwide. A meta-analysis of prospective human studies across the world demonstrated a consistent positive association between maternal exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) and children with obesity. The present study evaluates the association of maternal exposure to DDT and DDE with the risk of obesity in daughters during their mid-life in a prospective birth cohort with up to 53 years of follow-up.Methods:Gravidas’ blood was collected during their 1959–1967 enrollment into the prospective Child Health and Development Studies birth cohort in California. Their daughters aged 44–53 years had their height, weight, and waist circumference measured during a home visit to evaluate associations of daughters’ adiposity and relative risk of overweight and obesity with their mothers’ prenatal serum levels of DDT and DDE quantified by gas chromatograph-tandem mass spectrometer (n=511).Results:Maternal o,p’-DDT was positively associated with body mass index (beta=0.59 kg/m2 per ln ng/ml (95th percentile confidence interval, 95CI: 0.17, 1.00)) and waist circumference (beta=1.19 cm per ln ng/ml (95CI: 0.26, 2.13)) in multivariable models. Maternal o,p’-DDT was positively associated with a 26% (95CI: 6–49%) to 31% (95CI: 6–62%) higher risk of overweight and the same magnitude of additional risk for obesity, based on waist circumference and BMI definitions respectively, in multivariable models.Conclusions:These data indicate maternal DDT exposure is significantly associated with increased obesity risk among middle-aged women independent of the obesity definition, confounding, and obesity risk factors. Our findings suggest that policies supporting the use of DDT for malaria vector abatement need to consider the obesity risk as a health cost when weighing the benefits of using DDT in malaria vector control.

Abstract 646: Pre conception paternal DDT exposure and programming of metabolic dysfunction and breast cancer risk in offspring

Abstract Background: Breast cancer is the most common cancer in American women, being the second leading cause of cancer-related death in this group. Exposure to environmental chemicals, such as the pesticide DDT (dichlorodiphenyltrichloroethane), has been long suspected to be a contributing factor in the development of metabolic disease and breast cancer. For instance, early life (in utero and early childhood) exposure to DDT has been associated with increased breast cancer risk in women, and these findings are supported by animal studies. While maternal DDT exposure in pregnancy has been linked to metabolic syndrome and breast cancer risk in offspring, the effects of paternal DDT exposure in male germ-line reprogramming and phenotypes in their progeny has not been investigated. Here, we evaluated the effects of pre-conception paternal exposure to DDT on offspring’s metabolism and susceptibility of breast cancer, using a mouse model. Methods: Male mice were exposed to DDT (1.7mg/kg body weight) by oral gavage for two weeks. At the end of this period, DDT and control-vehicle (CO) were housed with female mice, with free access to a standard chow diet, for three days. Pregnancy onset was assessed by the presence of a vaginal plug. The weight and number of pups per litter were determined two days after birth. Pups were weaned from mothers at 21 days of age, fed a standard chow diet for the extent of the study and weighed weekly. Mammary tumors were induced by subcutaneous administration of 15mg of medroxyprogesterone to six-week-old female offspring, followed by oral administration of 1mg 7,12-dimethylbenz[a]anthracene once-a-week for 3 weeks. Results: Paternal DDT exposure reprogramed the sperm small non-coding RNA content. In line with that, DDT offspring had decreased birthweight (p=0.04) and weaning weight (p=0.01) compared to CO. Further, ancestral DDT exposure caused metabolic dysfunction in offspring (p<0.05) at 7 and 22 weeks of age. Further, female offspring of DDT exposed fathers showed alterations in mammary gland development with a non-significant increase in numbers of terminal end buds and lower rates of apoptosis. In line with that, our preliminary data suggest that ancestral paternal exposures to DDT increases breast cancer risk in offspring: Compared to CO, the DDT offspring presented a non-significant increase in mammary tumor incidence and shorter latency to first-tumor onset. In addition, tumor growth (volume) was significantly increased in DDT offspring compared to CO (p<0.01). In conclusion, our findings support a role for DDT exposure from the paternal lineage in metabolic dysfunction and increased breast cancer risk in their offspring. Citation Format: Raquel Santana Da Cruz, Hong Cao, Camille Castilho Fontelles, Apsra Nasir, M Idalia Cruz, Sonia de Assis. Pre conception paternal DDT exposure and programming of metabolic dysfunction and breast cancer risk in offspring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 646.

In utero and childhood DDT, DDE, PBDE and PCBs exposure and sex hormones in adolescent boys: The CHAMACOS study.

Dichlorodiphenyltrichloroethane (DDT), polybrominated diphenyl ether (PBDE) flame retardants, and polychlorinated biphenyls (PCBs) are believed to be endocrine-disrupting chemicals (EDCs) in humans and animals. The purpose of this study is to examine the relationship of in utero and childhood exposure to these purported EDCs and reproductive hormones in adolescent boys who participated in CHAMACOS, an ongoing birth cohort in California's Salinas Valley. We measured o,p'- and p,p'-DDT, p,p'-DDE, PBDEs and PCBs in serum collected from mothers during pregnancy or at delivery and from their sons at 9 years. We measured concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and total testosterone (T) from 234 of their sons at 12 years. In adjusted models, we found that a 10-fold increase in maternal prenatal serum concentrations of BDE-153 was associated with a 22.2% increase (95% CI: 1.0, 47.9) in FSH, a 96.6% increase (95% CI: 35.7, 184.7) in LH, and a 92.4% increase (95% CI: 20.9, 206.2) increase in T. Similarly, BDE-100 concentrations were associated with increases in boys' LH levels. A 10-fold increase in total prenatal ΣPCBs was associated with a 64.5% increase (95% CI: 8.6, 149.0) in FSH, primarily driven by non- dioxin-like congeners. Boys' hormone levels were only marginally associated with prenatal DDT or DDE in primary models, but when boys' Tanner stage at age 12 was added to models, prenatal maternal DDT levels were associated with decreases in LH (adjusted percent change per 10-fold increase=-18.5%, 95% CI: -29.8, -5.4) and T (percent change=-18.2%, 95% CI: -30.2, -4.2) and DDE with LH (percent change=-18.3%, 95% CI: -32.9, -0.6). Exposures measured in the children's serum at 9 years also showed associations between BDE-153 and ΣPCBs. However, there is evidence that these associations appear to be mediated by child BMI. This study suggests associations on male hormones of 12year old boys related to exposure to certain EDC exposure prenatally. The implications on future reproductive function in puberty and adulthood should be determined.

Prenatal DDT and DDE exposure and child IQ in the CHAMACOS cohort

Although banned in most countries, dichlorodiphenyl-trichloroethane (DDT) continues to be used for vector control in some malaria endemic areas. Previous findings from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort study found increased prenatal levels of DDT and its breakdown product dichlorodiphenyl-dichloroethylene (DDE) to be associated with altered neurodevelopment in children at 1 and 2years of age. In this study, we combined the measured maternal DDT/E concentrations during pregnancy obtained for the prospective birth cohort with predicted prenatal DDT and DDE levels estimated for a retrospective birth cohort. Using generalized estimating equation (GEE) and linear regression models, we evaluated the relationship of prenatal maternal DDT and DDE serum concentrations with children's cognition at ages 7 and 10.5years as assessed using the Full Scale Intelligence Quotient (IQ) and 4 subtest scores (Working Memory, Perceptual Reasoning, Verbal Comprehension, and Processing Speed) of the Wechsler Intelligence Scale for Children (WISC). In GEE analyses incorporating both age 7 and 10.5 scores (n=619), we found prenatal DDT and DDE levels were not associated with Full Scale IQ or any of the WISC subscales (p-value>0.05). In linear regression analyses assessing each time point separately, prenatal DDT levels were inversely associated with Processing Speed at age 7years (n=316), but prenatal DDT and DDE levels were not associated with Full Scale IQ or any of the WISC subscales at age 10.5years (n=595). We found evidence for effect modification by sex. In girls, but not boys, prenatal DDE levels were inversely associated with Full Scale IQ and Processing Speed at age 7years. We conclude that prenatal DDT levels may be associated with delayed Processing Speed in children at age 7years and the relationship between prenatal DDE levels and children's cognitive development may be modified by sex, with girls being more adversely affected.

Detecting Associations between Early-Life DDT Exposures and Childhood Growth Patterns: A Novel Statistical Approach.

It has been hypothesized that environmental exposures at key development periods such as in utero play a role in childhood growth and obesity. To investigate whether in utero exposure to endocrine-disrupting chemicals, dichlorodiphenyltrichloroethane (DDT) and its metabolite, dichlorodiphenyldichloroethane (DDE), is associated with childhood physical growth, we took a novel statistical approach to analyze data from the CHAMACOS cohort study. To model heterogeneity in the growth patterns, we used a finite mixture model in combination with a data transformation to characterize body mass index (BMI) with four groups and estimated the association between exposure and group membership. In boys, higher maternal concentrations of DDT and DDE during pregnancy are associated with a BMI growth pattern that is stable until about age five followed by increased growth through age nine. In contrast, higher maternal DDT exposure during pregnancy is associated with a flat, relatively stable growth pattern in girls. This study suggests that in utero exposure to DDT and DDE may be associated with childhood BMI growth patterns, not just BMI level, and both the magnitude of exposure and sex may impact the relationship.

In-Utero Exposure to Dichlorodiphenyltrichloroethane and Cognitive Development Among Infants and School-aged Children

Dichlorodiphenyltrichloroethane (DDT) continues to be used for control of infectious diseases in several countries. In-utero exposure to DDT and dichlorodiphenyldichloroethylene (DDE) has been associated with developmental and cognitive impairment among children. We examined this association in an historical cohort in which the level of exposure was greater than in previous studies. The association of in-utero DDT and DDE exposure with infant and child neurodevelopment was examined in 1100 subjects in the Collaborative Perinatal Project, a prospective birth cohort enrolling pregnant women from 12 study centers in the United States from 1959 to 1965. Maternal DDT and DDE concentrations were measured in archived serum specimens. Infant mental and motor development was assessed at age 8 months using the Bayley Scales of Infant Development, and child cognitive development was assessed at age 7 years, using the Wechsler Intelligence Scale for Children. Although levels of DDT and DDE were relatively high in this population (median DDT concentration, 8.9 μg/L; DDE, 24.5 μg/L), neither were related to Mental or Psychomotor Development scores on the Bayley Scales nor to Full-Scale Intelligence Quotient at 7 years of age. Categorical analyses showed no evidence of dose- response for either maternal DDT or DDE, and estimates of the association between continuous measures of exposure and neurodevelopment were indistinguishable from 0. Adverse associations were not observed between maternal serum DDT and DDE concentrations and offspring neurodevelopment at 8 months or 7 years in this cohort.

Levels of DDT and its metabolites in placenta, maternal and cord blood and their potential influence on neonatal anthropometric measures

Previous studies of in utero exposure to dichlorodiphenyltrichloroethane (DDT) have shown mixed results for the harmful effects on fetal growth and development. This cross-sectional study was designed to: (1) examine the extent of DDT exposure in 1578 women, aged 28.5±6.0 who delivered between June 2005 and 2006 in the area of Al-Kharj, Saudi Arabia; and (2) assess its influence on neonatal anthropometric measurement of newly born babies. DDT and its metabolites, namely 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (p,p′-DDE), 1,1-dichloro-2,2-bis (p-chlorophenyl) ethane (p,p′-DDD) and 1,1,1-trichloro-2,2′ bis (p-chlorophenyl) ethane (p,p′-DDT) were measured in cord and maternal serum as well as placenta by Gas Chromatography coupled with an Electron Capture Detector (GC/ECD). p,p′-DDE was detected in 28.3% of cord and 54.4% of maternal serum, reflecting past exposure, whereas the p,p′-DDT was only found in 0.46% cord and 1.2% maternal samples. As expected the p,p′-DDE cord levels (0.197±0.961μg/L) were 2.8 times lower than the maternal levels (0.551±1.778μg/L), and both were significantly correlated (r=0.517) suggesting its transplacental transfer. The picture was different in placental tissues. p,p′-DDE and p,p′-DDT were detected in 84% and 99% of placental tissues, with the highest p,p′-DDT in placental tissues (29.62±158.282µg/kg dry wt.) compare to p,p′-DDE (10.167±18.851μg/kg dry wt.). In general, the presence of DDT metabolites in our participants indicates that these chemicals are still relevant despite the fact that they have been banned or restricted in the study area for many years. Our results support the view for an association between low in utero exposure to DDT and the anthropometric development of the fetus leading to a reduction in its head circumference, crown–heel length, birth weight and birth height. Since the reduction in these measures was independent of gestational age and/or preterm births, our findings suggest a detrimental effect of the DDT exposure on fetal growth. Neonatal anthropometric measures are considered as an important tool to detect newborns at higher risk of morbidity and impairment of growth. Efforts should be made to decrease exposure of women of reproductive age and to examine maternal DDT exposure in relation to long-term impact on health.

Maternal DDT and DDE Exposure and Time to Pregnancy

Maternal DDT and DDE Exposure and Time to Pregnancy

Maternal DDT Exposures in Relation to Fetal and 5-Year Growth

Dichlorodiphenyltrichloroethane (DDT) is an organochlorine pesticide still used in areas of the world where malaria vector control is needed. Few studies have examined in utero exposures to DDT in relation to fetal and early childhood growth in populations with substantial exposure to DDT. Furthermore, only a portion of these studies have investigated in utero exposures and growth during childhood. To assess the role of in utero exposures to DDT on fetal and early childhood growth, we analyzed data from mothers and children who participated in the Child Health and Development Study (CHDS), a cohort study of 20,754 women and their pregnancies conducted in the San Francisco Bay area during the 1960s. We measured p,p'-DDE, o,p'-DDT, and p,p'-DDT concentrations from the stored sera of 399 women collected during pregnancy. Outcomes were measured at the child's birth and at 5 years of age. Maternal p,p'-DDE concentrations were considerable in this study, averaging 6.9 micrograms per gram lipid. After covariate adjustment, a small increase in gestational age was observed with increases in p,p'-DDT and o,p'-DDT, but there was no association with p,p'-DDE. At 5 years of age, an increase from the 25th to the 75th percentile in p,p'-DDE was related to a 2-mm increase in head circumference (95% confidence interval = 0 to 4). Overall effect sizes were small and imprecise. Furthermore, there was little evidence of specificity for a given outcome or exposure at either age. At the concentrations studied in this sample, DDT compounds did not appear to impair fetal or 5-year growth.

Maternal DDT Exposures in Relation to Fetal and 5-Year Growth

Maternal DDT Exposures in Relation to Fetal and 5-Year Growth

MEASURING THE EFFECTS OF DDT AND DDE ON PRETERM DELIVERY, SMALL-FOR-GESTATIONAL AGE BIRTH AND LOW BIRTHWEIGHT BIRTH

ISEE-473 Objective: Though banned in the United States since 1972, the pesticide 1,1,1-trichloro-2,2’-bis(p-chlorophenyl)ethane (DDT) is used elsewhere for mosquito control. Its human health costs and benefits thus remain a current concern. DDT, and its persistent metabolite DDE, have been associated with negative reproductive outcomes in birds, rabbits and sea lions. However, there are inconsistencies regarding exposure to DDT and effects on human health. This study was designed to evaluate the effects of serum levels of DDT and its major metabolite DDE on three adverse human birth outcomes - preterm delivery, small-for-gestational-age birth and low birthweight. Methods: Nested case-control study. We studied a sample of male live births from a longitudinal cohort study of 20,754 pregnancies that occurred between 1959 and 1967 (a period of high domestic DDT usage in the United States). The 283 male subjects included in this analysis were randomly selected controls from another study of the effects of organochlorine pesticides on male genital anomalies. Birth outcome data and maternal demographic/behavioral data were collected through maternal interviews and abstracted medical records. Maternal serum samples were taken during pregnancy and post-partum. Serum DDT and DDE were determined by gas chromatography/electron capture detection (GC/ECD). Data were analyzed using multivariate logistic regression for preterm delivery and small-for-gestational age birth and linear regression for birthweight. Results: Mean serum levels for DDT and DDE were 1.6 and 5.9 μg/g lipid, respectively. Variables identified as significant in bivariate analysis against each outcome variable were included as covariates in multivariate analysis. Preliminary findings indicate that maternal DDT and DDE levels, controlling for a range of demographic and behavioral variables associated with birth outcomes (i.e., age, race, education, marital status, income, occupation, place of birth, parity, BMI, and smoking and alcohol use) do not predict preterm delivery (n=23); small-for-gestational age birth (n=28), or low birthweight (n=13). Final results of regression analyses, including odds ratios and confidence intervals, will be presented. Discussion: The effect of DDT and DDE on human birth outcomes in this study appears null. However, we were limited by the small size of the study and the fact that we were only able to examine live births. Considering the persistence of DDT in the environment and its role in malaria control, further studies using more robust data should continue to assess this relationship.

Concentraciones de DDT/DDE y riesgo de hipospadias: un estudio piloto de casos y controles

To evaluate the association between maternal serum DDT/DDE levels and risk of hypospadias. A case-control study in Mexico City was conducted during 1997-1999 among 41 subjects with hypospadias and 28 controls. Blood samples were obtained from study subjects. Information was obtained using a standardized questionnaire. Data were analyzed using multivariate logistic regression models. Maternal DDT and DDE levels showed no association with hypospadias (OR 1.13; 95% CI 0.24-5.29 and OR = 0.48; 95% CI 0.15-1.60, respectively). Associated factors were older age of mothers (OR 8.69; 95% CI 1.69-44.9), and working during pregnancy (OR 4.68; 95% CI 1.15-18.9). Information about the endocrine effects of different levels of DDT/DDE in human subjects is scarce; dosage may be a determinant factor of the type of effect. The English version of this paper is available at:http://www.insp.mx/salud/index.html.