Female Reproductive Impacts

Arbuckle et al., 1999

Arbuckle TE, Savitz DA, Mery LS, Curtis KM, “Exposure to phenoxy herbicides and the risk of spontaneous abortion,” Epidemiology, 1999, 10:6.

ABSTRACT:  The Ontario Farm Family Health Study was designed to assess retrospectively the potential adverse effects of exposure to pesticides on pregnancy. Information on the health and life style of approximately 2,000 farm couples, as well as a history of use of pesticides on the farm, was collected by questionnaire. This analysis focuses on pre- and postconception exposure to phenoxy herbicides and the risk of spontaneous abortion using the complete (to date) pregnancy history for each woman. Preconception exposure (from 3 months before conception to the month of conception) was weakly associated with the risk of spontaneous abortion at <20 weeks’ gestation [adjusted odds ratio (OR) = 1.1; 95% confidence interval (CI) = 0.6-1.9]. When the analyses were restricted to spontaneous abortions of <12 weeks, the risk was more than doubled (adjusted OR = 2.5; 95% CI = 1.0-6.4), but the results were sensitive to the cutpoint used. If the husband did not normally wear protective equipment during application, the crude OR for early spontaneous abortions was 5.0 (95% CI = 0.7-36.2). Exposure to phenoxy herbicides during the first trimester was generally not associated with increased risk of spontaneous abortion. The results suggest a possible role of preconception (possibly paternal) exposures to phenoxy herbicides in the risk of early spontaneous abortions.

Arbuckle et al., 2001

Arbuckle TE, Lin Z, Mery LS., “An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population,” Environmental Health Perspectives, 2001, 109: 8.

ABSTRACT: The toxicity of pesticides on human reproduction is largely unknown–particularly how mixtures of pesticide products might affect fetal toxicity. The Ontario Farm Family Health Study collected data by questionnaire on the identity and timing of pesticide use on the farm, lifestyle factors, and a complete reproductive history from the farm operator and eligible couples living on the farm. A total of 2,110 women provided information on 3,936 pregnancies, including 395 spontaneous abortions. To explore critical windows of exposure and target sites for toxicity, we examined exposures separately for preconception (3 months before and up to month of conception) and postconception (first trimester) windows and for early (< 12 weeks) and late (12-19 weeks) spontaneous abortions. We observed moderate increases in risk of early abortions for preconception exposures to phenoxy acetic acid herbicides [odds ratio (OR) = 1.5; 95% confidence interval (CI), 1.1-2.1], triazines (OR = 1.4; 95% CI, 1.0-2.0), and any herbicide (OR = 1.4; 95% CI, 1.1-1.9). For late abortions, preconception exposure to glyphosate (OR = 1.7; 95% CI, 1.0-2.9), thiocarbamates (OR = 1.8; 95% CI, 1.1-3.0), and the miscellaneous class of pesticides (OR = 1.5; 95% CI, 1.0-2.4) was associated with elevated risks. Postconception exposures were generally associated with late spontaneous abortions. Older maternal age (> 34 years of age) was the strongest risk factor for spontaneous abortions, and we observed several interactions between pesticides in the older age group using Classification and Regression Tree analysis. This study shows that timing of exposure and restricting analyses to more homogeneous endpoints are important in characterizing the reproductive toxicity of pesticides.  FULL TEXT

Benachour and Seralini, 2009.

Benachour N, Séralini GE, “Glyphosate formulations induce apoptosis and necrosis in human umbilical, embryonic, and placental cell,” Chemical Research in Toxicology, 2009, 22(1):97-105, doi: 10.1021/ tx800218n.

ABSTRACT: We have evaluated the toxicity of four glyphosate (G)-based herbicides in Roundup formulations, from 10(5) times dilutions, on three different human cell types. This dilution level is far below agricultural recommendations and corresponds to low levels of residues in food or feed. The formulations have been compared to G alone and with its main metabolite AMPA or with one known adjuvant of R formulations, POEA. HUVEC primary neonate umbilical cord vein cells have been tested with 293 embryonic kidney and JEG3 placental cell lines. All R formulations cause total cell death within 24 h, through an inhibition of the mitochondrial succinate dehydrogenase activity, and necrosis, by release of cytosolic adenylate kinase measuring membrane damage. They also induce apoptosis via activation of enzymatic caspases 3/7 activity. This is confirmed by characteristic DNA fragmentation, nuclear shrinkage (pyknosis), and nuclear fragmentation (karyorrhexis), which is demonstrated by DAPI in apoptotic round cells. G provokes only apoptosis, and HUVEC are 100 times more sensitive overall at this level. The deleterious effects are not proportional to G concentrations but rather depend on the nature of the adjuvants. AMPA and POEA separately and synergistically damage cell membranes like R but at different concentrations. Their mixtures are generally even more harmful with G. In conclusion, the R adjuvants like POEA change human cell permeability and amplify toxicity induced already by G, through apoptosis and necrosis. The real threshold of G toxicity must take into account the presence of adjuvants but also G metabolism and time-amplified effects or bioaccumulation. This should be discussed when analyzing the in vivo toxic actions of R. This work clearly confirms that the adjuvants in Roundup formulations are not inert. Moreover, the proprietary mixtures available on the market could cause cell damage and even death around residual levels to be expected, especially in food and feed derived from R formulation-treated crops.

Chevrier et al., 2011

Cecile Chevrier, Gwendolina Limon, Christine Monfort, Florence Rouget, Ronan Garlantezec, et al., “Urinary biomarkers of prenatal atrazine exposure and adverse birth outcomes in the PELAGIE birth cohort,” Environmental Health Perspectives, 2011, 119:7, DOI: 10.1289/EHP.100277.


BACKGROUND:  Despite evidence of atrazine toxicity in developing organisms from experimental studies, few studies—and fewer epidemiologic investigations—have examined the potential effects of prenatal exposure.

OBJECTIVES: We assessed the association between adverse birth outcomes and urinary biomarkers of prenatal atrazine exposure, while taking into account exposures to other herbicides used on corn crops (simazine, alachlor, metolachlor, and acetochlor).

METHODS: This study used a case-cohort design nested in a prospective birth cohort conducted in the Brittany region of France from 2002 through 2006. We collected maternal urine samples to examine pesticide exposure biomarkers before the 19th week of gestation.

RESULTS: We found quantifiable levels of atrazine or atrazine mercapturate in urine samples from 5.5% of 579 pregnant women, and dealkylated and identified hydroxylated triazine metabolites in 20% and 40% of samples, respectively. The presence versus absence of quantifiable levels of atrazine or a specific atrazine metabolite was associated with fetal growth restriction [odds ratio (OR) = 1.5; 95% confidence interval (CI), 1.0–2.2] and small head circumference for sex and gestational age (OR = 1.7; 95% CI, 1.0–2.7). Associations with major congenital anomalies were not evident with atrazine or its specific metabolites. Head circumference was inversely associated with the presence of quantifiable urinary metolachlor.

CONCLUSIONS: This study is the first to assess associations of birth outcomes with multiple urinary biomarkers of exposure to triazine and chloroacetanilide herbicides. Evidence of associations with adverse birth outcomes raises particular concerns for countries where atrazine is still in use.  FULL TEXT

Colborn and Carroll, 2007

Colborn, Theo, Lynn Carroll,  “Pesticides, Sexual Development, Reproduction,and Fertility: Current Perspective and Future Direction,” Human and Ecological Risk Assessment, 2007, 13:5.

ABSTRACT: Improvements in chemical analytical technology and non-invasive sampling protocols have made it easier to detect pesticides and their metabolites at very low concentrations in human tissues. Monitoring has revealed that pesticides penetrate both maternal and paternal reproductive tissues and organs, thus providing a pathway for initiating harm to their offspring starting before fertilization throughout gestation and lactation. This article explores the literature that addresses the parental pathway of exposure to pesticides. We use DDT/DDE as a model for chemicals that oftentimes upon exposure have no apparent, immediate health impacts, or cause no obvious birth defects, and are seldom linked with cancer. Their health effects are overlooked because they are invisible and not life threatening—but might have significant health, social, and economic impacts at the individual and population levels. The purpose of this article is to demonstrate the necessity to develop new approaches for determining the safety of pesticides and the need for innovative regulatory policy to protect human and environmental health.

Crews et al., 2007

David Crews, Andrea C. Gore, Timothy S. Hsu, Nygerma L. Dangleben, Michael Spinetta, Timothy Schallert, Matthew D. Anway, and Michael K. Skinner, “Transgenerational epigenetic imprints on mate preference,” PNAS, 2007, 104:14, DOI: 10.1073/PNAS.0610410104.


Environmental contamination by endocrine-disrupting chemicals (EDC) can have epigenetic effects (by DNA methylation) on the germ line and promote disease across subsequent generations. In natural populations, both sexes may encounter affected as well as unaffected individuals during the breeding season, and any diminution in attractiveness could compromise reproductive success. Here we examine mate preference in male and female rats whose progenitors had been treated with the antiandrogenic fungicide vinclozolin. This effect is sex-specific, and we demonstrate that females three generations removed from the exposure discriminate and prefer males who do not have a history of exposure, whereas similarly epigenetically imprinted males do not exhibit such a preference. The observations suggest that the consequences of EDCs are not just transgenerational but can be ‘‘transpopulational’’, because in many mammalian species, males are the dispersing sex. This result indicates that epigenetic transgenerational inheritance of EDC action represents an unappreciated force in sexual selection. Our observations provide direct experimental evidence for a role of epigenetics as a determinant factor in evolution.  FULL TEXT

Donauer et al., 2016

Donauer, Stephanie, Mekibib Altaye, Yingying Xu, Heidi Sucharew, Paul Succop, Antonia M. Calafat, Jane C. Khoury, Bruce Lanphear, Kimberly Yolton, “An Observational Study to Evaluate Associations Between Low-Level Gestational Exposure to Organophosphate Pesticides and Cognition During Early Childhood,” American Journal of Epidemiology, 2016, 184:5.


Prenatal exposure to organophosphate pesticides, which is ubiquitous, may be detrimental to neurological development. We examined 327 mother/infant pairs in Cincinnati, Ohio, between 2003 and 2006 to determine associations between prenatal exposure to organophosphate pesticides and neurodevelopment. Twice during pregnancy urinary concentrations of 6 common dialkylphosphates, nonspecific metabolites of organophosphate pesticides, were measured. Aggregate concentrations of diethylphosphates, dimethylphosphates, and total dialkylphosphates were calculated. Bayley Scales of Infant Development, Second Edition-Mental and Psychomotor Developmental indices were administered at ages 1, 2, and 3 years, the Clinical Evaluation of Language Fundamentals-Preschool, Second Edition, at age 4, and the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, at age 5. Mothers with higher urinary total dialkylphosphate concentrations reported higher levels of socioeconomic status and increased fresh fruit and vegetable intake. We found no associations between prenatal exposure to organophosphate pesticides and cognition at 1-5 years of age. In our cohort, exposure to organophosphate pesticides during pregnancy was not associated with cognition during early childhood. It is possible that a higher socioeconomic status and healthier diet may protect the fetus from potential adverse associations with gestational organophosphate pesticide exposure, or that dietary exposure to the metabolites is innocuous and not an ideal measure of exposure to the parent compound.

Garry et al., 1996

Garry VF, Schreinemachers D, Harkins ME, Griffith J, “Pesticide appliers, biocides, and birth defects in rural Minnesota,” Environmental Health Perspectives, 1996, 104:4.

ABSTRACT: Earlier studies by our group suggested the possibility that offspring of pesticide appliers might have increased risks of birth anomalies. To evaluate this hypothesis, 935 births to 34,772 state-licensed, private pesticide appliers in Minnesota occurring between 1989 and 1992 were linked to the Minnesota state birth registry containing 210,723 live births in this timeframe. The birth defect rate for all birth anomalies was significantly increased in children born to private appliers. Specific birth defect categories, circulatory/respiratory, urogenital, and musculoskeletal/integumental, showed significant increases. For the general population and for appliers, the birth anomaly rate differed by corp-growing region. Western Minnesota, a major wheat, sugar beet, and potato growing region, showed the highest rate of birth anomalies per/1000 live births: 30.0 for private appliers versus 26.9 for the general population of the same region. The lowest rates, 23.7/1000 for private appliers versus 18.3/1000 for the general population, occurred in noncorp regions. The highest frequency of use of chlorophenoxy herbicides and fungicides also occurred in western Minnesota. Births in the general population of western Minnesota showed a significant increase in birth anomalies in the same three birth anomaly categories as appliers and for central nervous system anomalies. This increase was most pronounced for infants conceived in the spring. The seasonal effect did not occur in other regions. The male/female sex ratio for the four birth anomaly categories of interest in areas of high phenoxy herbicide/fungicide use is 2.8 for appliers versus 1.5 for the general population of the same region (p = 0.05). In minimal use regions, this ratio is 2.1 for appliers versus 1.7 for the general population. The pattern of excess frequency of birth anomalies by pesticide use, season, and alteration of sex ratio suggests exposure-related effects in appliers and the general population of the crop-growing region of western Minnesota.  FULL TEXT

Garry et al., 2002a

Garry VF, Harkins M, Lyubimov A, Erickson L, Long L., “Reproductive outcomes in the women of the Red River Valley of the north. I. The spouses of pesticide applicators: pregnancy loss, age at menarche, and exposures to pesticides,” Journal of Toxicology and Environmental Health – Part A, 2002, 65:11.

ABSTRACT: In the current study, there was a modest but significant increase in risk (1.6- to 2-fold) for miscarriages and/or fetal loss occurring throughout the year in the spouses of applicators who use fungicides. There is a surprisingly significant deficit in the number of male children born to the spouses of fungicide applicators. First-trimester miscarriages occur most frequently in the spring, during the time when herbicides are applied. Use of sulfonylurea (odds ratio OR = 2.1), imidizolinone (OR = 2.6) containing herbicides, and the herbicide combination Cheyenne (OR = 2.9) by male applicators was statistically associated with increased miscarriage risk in the spring. Limited survey data from women who are the spouses of applicators did not show major alterations of long-term endocrinologic status (menarche, menopause, endometriosis). With regard to personal pesticide exposures, only women who engaged in pesticide application where there is direct exposure to these products are at demonstrable risk (OR = 1.8) for miscarriage. It was hypothesized that the overall reproductive toxicity observed in this population is, for the greater part, a male-mediated event. Clarification of exposure events leading to reproductive toxicity through direct measurements of exposure in both men and women is needed to resolve this issue.

Manikkam et al., 2012

Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK, “Pesticide and insect repellent mixture (permethrin and DEET) induces epigenetic transgenerational inheritance of disease and sperm epimutations,” Reproductive Toxicology, 2012,  34:4,  DOI: 10.1016/j.reprotox.2012.08.010.

ABSTRACT: Environmental compounds are known to promote epigenetic transgenerational inheritance of disease. The current study was designed to determine if a “pesticide mixture” (pesticide permethrin and insect repellent N,N-diethyl-meta-toluamide, DEET) promotes epigenetic transgenerational inheritance of disease and associated DNA methylation epimutations in sperm. Gestating F0 generation female rats were exposed during fetal gonadal sex determination and the incidence of disease evaluated in F1 and F3 generations. There were significant increases in the incidence of total diseases in animals from pesticide lineage F1 and F3 generation animals. Pubertal abnormalities, testis disease, and ovarian disease (primordial follicle loss and polycystic ovarian disease) were increased in F3 generation animals. Analysis of the pesticide lineage F3 generation sperm epigenome identified 363 differential DNA methylation regions (DMR) termed epimutations. Observations demonstrate that a pesticide mixture (permethrin and DEET) can promote epigenetic transgenerational inheritance of adult onset disease and potential sperm epigenetic biomarkers for ancestral environmental exposures.  FULL TEXT