Bibliography Tag: female reproductive impacts

Berkowitz et al., 2004

Berkowitz, G. S., Wetmur, J. G., Birman-Deych, E., Obel, J., Lapinski, R. H., Godbold, J. H., Holzman, I. R., & Wolff, M. S.; “In utero pesticide exposure, maternal paraoxonase activity, and head circumference;” Environmental Health Perspectives, 2004, 112(3), 388-391; DOI: 10.1289/ehp.6414.


Although the use of pesticides in inner-city homes of the United States is of considerable magnitude, little is known about the potentially adverse health effects of such exposure. Recent animal data suggest that exposure to pesticides during pregnancy and early life may impair growth and neurodevelopment in the offspring. To investigate the relationship among prenatal pesticide exposure, paraoxonase (PON1) polymorphisms and enzyme activity, and infant growth and neurodevelopment, we are conducting a prospective, multiethnic cohort study of mothers and infants delivered at Mount Sinai Hospital in New York City. In this report we evaluate the effects of pesticide exposure on birth weight, length, head circumference, and gestational age among 404 births between May 1998 and May 2002. Pesticide exposure was assessed by a prenatal questionnaire administered to the mothers during the early third trimester as well as by analysis of maternal urinary pentachlorophenol levels and maternal metabolites of chlorpyrifos and pyrethroids. Neither the questionnaire data nor the pesticide metabolite levels were associated with any of the fetal growth indices or gestational age. However, when the level of maternal PON1 activity was taken into account, maternal levels of chlorpyrifos above the limit of detection coupled with low maternal PON1 activity were associated with a significant but small reduction in head circumference. In addition, maternal PON1 levels alone, but not PON1 genetic polymorphisms, were associated with reduced head size. Because small head size has been found to be predictive of subsequent cognitive ability, these data suggest that chlorpyrifos may have a detrimental effect on fetal neurodevelopment among mothers who exhibit low PON1 activity. FULL TEXT

Almeida et al., 2017

Almeida, L. L., Teixeira, A. A. C., Soares, A. F., Cunha, F. M. D., Silva, V. A. D. Junior, Vieira Filho, L. D., & Wanderley-Teixeira, V.; “Effects of melatonin in rats in the initial third stage of pregnancy exposed to sub-lethal doses of herbicides;” Acta Histochemica, 2017, 119(3), 220-227; DOI: 10.1016/j.acthis.2017.01.003.


Exposure to the herbicides Paraquat (PQ) and Roundup((R)) may cause cell lesions due to an increase in oxidative stress levels in different biological systems, even in the reproductive system.

OBJECTIVE: Evaluate the possible changes in reproductive parameters and hepatic, as well as its prevention by simultaneous application of melatonin.

METHODS: Thirty-five female rats at the age of 3 months were divided into seven groups: three groups exposed to sub-lethal doses of the herbicides PQ (50mg/kg) and Roundup((R)) (500mg/kg) (n=5, G2, G3 and G4); three groups exposed to herbicides and simultaneous treatment with 10mg/kg of Melatonin (n=5, G5, G6 and G7) and control group (n=5, G1) from the first to the seventh day of pregnancy. On the seventh day of pregnancy, the rats were anesthetized and euthanized, followed by laparotomy to remove their reproductive tissues and liver. Body and ovary weights were taken and the number of implantation sites, corpora lutea, preimplantation losses, implantation rates were counted and histopathology of the implantation sites, morphometry of the surface and glandular epithelia of endometrium and hepatic oxidative stress were undertaken.

RESULTS: The present study shows the decrease in body and ovary weight, decrease in the number of implantation sites, implantation rate, in the total number of corpora lutea and increase of preimplantation percentages were observed when compared to the G1: Fig. 1 and Table 1, (p>0.001 ANOVA/Tukey). The histopathological analysis of the implantation sites showed a disorder of the cytotrophoblast and cell degeneration within the blastocyst cavity in Fig. 4. Morphometry revealed a reduction in surface and glandular epithelia and in the diameter of the endometrial glands (Table 2; p>0.05 ANOVA/Tukey), whereas in liver, serum levels of thiobarbituric acid reactive substances (TBARS) were found to be significantly elevated (Fig. 2; p>0.001; p>0.05 ANOVA/Tukey), and serum level of reduced glutathione (GSH) was significantly lower (Fig. 3; p>0.001 ANOVA/Tukey). However, treatments with melatonin exhibited improvements in reproductive parameters, as well as reduced lesions in the implantation sites (Fig. 4.) and in serum levels TBARS (Fig. 2; p>0.001 ANOVA/Tukey), serum levels GSH (Fig. 3; p>0.001; p>0.05 ANOVA/Tukey).

CONCLUSIONS: These results reveal that melatonin is a protective agent against experimentally induced maternal/embryo toxicity with herbicides and favoring normalization of reproductive parameters and hepatic.


Dechartres et al., 2019

Dechartres, J., Pawluski, J. L., Gueguen, M. M., Jablaoui, A., Maguin, E., Rhimi, M., & Charlier, T. D.; “Glyphosate and glyphosate-based herbicide exposure during the peripartum period affects maternal brain plasticity, maternal behaviour and microbiome;” Journal of Neuroendocrinology, 2019, 31(9), e12731; DOI: 10.1111/jne.12731.


Glyphosate is found in a large array of non-selective herbicides such as Roundup(R) (Monsanto, Creve Coeur, MO, USA) and is by far the most widely used herbicide. Recent work in rodent models suggests that glyphosate-based herbicides during development can affect neuronal communication and result in altered behaviours, albeit through undefined mechanisms of action. To our knowledge, no study has investigated the effects glyphosate or its formulation in herbicide on maternal behaviour and physiology. In the present study, relatively low doses of glyphosate (5 mg kg(-1) d(-1) ), Roundup(R) (5 mg kg(-1) d(-1) glyphosate equivalent), or vehicle were administered by ingestion to Sprague-Dawley rats from gestational day (GD) 10 to postpartum day (PD)22. The treatments significantly altered licking behaviour toward pups between PD2 and PD6. We also show in the dams at PD22 that Roundup exposure affected the maturation of doublecortin-immunoreactive new neurones in the dorsal dentate gyrus of the hippocampus of the mother. In addition, the expression of synaptophysin was up-regulated by glyphosate in the dorsal and ventral dentate gyrus and CA3 regions of the hippocampus, and down-regulated in the cingulate gyrus. Although a direct effect of glyphosate alone or its formulation on the central nervous system is currently not clear, we show that gut microbiota is significantly altered by the exposure to the pesticides, with significant alteration of the phyla Bacteroidetes and Firmicutes. This is the first study to provide evidence that glyphosate alone or in formulation (Roundup) differentially affects maternal behaviour and modulates neuroplasticity and gut microbiota in the mother. FULL TEXT

Lorenz et al., 2019

Lorenz, V., Milesi, M. M., Schimpf, M. G., Luque, E. H., & Varayoud, J.; “Epigenetic disruption of estrogen receptor alpha is induced by a glyphosate-based herbicide in the preimplantation uterus of rats;” Molecular and Cellular Endocrinology, 2019, 480, 133-141; DOI: 10.1016/j.mce.2018.10.022.


Previously, we have shown that perinatal exposure to a glyphosate-based herbicide (GBH) induces implantation failures in rats. Estrogen receptor alpha (ERalpha) is critical for successful implantation. ERalpha transcription is under the control of five promoters (E1, OT, O, ON, and OS), which yield different transcripts. Here, we studied whether perinatal exposure to a GBH alters uterine ERalpha gene expression and prompts epigenetic modifications in its regulatory regions during the preimplantation period. Pregnant rats (F0) were orally treated with 350mg glyphosate/kg bw/day through food from gestational day (GD) 9 until weaning. F1 females were bred, and uterine samples were collected on GD5 (preimplantation period). ERalpha mRNA levels and its transcript variants were evaluated by RT-qPCR. Enzyme-specific restriction sites and predicted transcription factors were searched in silico in the ERalpha promoter regions to assess the methylation status using the methylation-sensitive restriction enzymes-PCR technique. Post-translational modifications of histones were studied by the chromatin immunoprecipitation assay. GBH upregulated the expression of total ERalpha mRNA by increasing the abundance of the ERalpha-O transcript variant. In addition, different epigenetic changes were detected in the O promoter. A decrease in DNA methylation was observed in one of the three sites evaluated in the O promoter. Moreover, histone H4 acetylation and histone H3 lysine 9 trimethylation (H3K9me3) were enriched in the O promoter in GBH-exposed rats, whereas H3K27me3 was decreased. All these alterations could account for the increase in ERalpha gene expression. Our findings show that perinatal exposure to a GBH causes long-term epigenetic disruption of the uterine ERalpha gene, which could be associated with the GBH-induced implantation failures. FULL TEXT


Rattan and Flaws, 2019

Rattan, S., & Flaws, J. A.; “The epigenetic impacts of endocrine disruptors on female reproduction across generationsdagger;” Biology of Reproduction, 2019, 101(3), 635-644; DOI: 10.1093/biolre/ioz081.


Humans and animals are repeatedly exposed to endocrine disruptors, many of which are ubiquitous in the environment. Endocrine disruptors interfere with hormone action; thus, causing non-monotonic dose responses that are atypical of standard toxicant exposures. The female reproductive system is particularly susceptible to the effects of endocrine disruptors. Likewise, exposures to endocrine disruptors during developmental periods are particularly concerning because programming during development can be adversely impacted by hormone level changes. Subsequently, developing reproductive tissues can be predisposed to diseases in adulthood and these diseases can be passed down to future generations. The mechanisms of action by which endocrine disruptors cause disease transmission to future generations are thought to include epigenetic modifications. This review highlights the effects of endocrine disruptors on the female reproductive system, with an emphasis on the multi- and transgenerational epigenetic effects of these exposures. FULL TEXT

Ingaramo et al., 2020

Ingaramo, P., Alarcon, R., Munoz-de-Toro, M., & Luque, E. H.; “Are glyphosate and glyphosate-based herbicides endocrine disruptors that alter female fertility?;” Molecular and Cellular Endocrinology, 2020, 110934; DOI: 10.1016/j.mce.2020.110934.


Numerous evidences have alerted on the toxic effects of the exposure to glyphosate on living organisms. Glyphosate is the herbicide most used in crops such as maize and soybean worldwide, which implies that several non-target species are at a high risk of exposure. Although the Environmental Protection Agency (EPA-USA) has reaffirmed that glyphosate is safe for users, there are controversial studies that question this statement. Some of the reported effects are due to exposure to high doses; however, recent evidences have shown that exposure to low doses could also alter the development of the female reproductive tract, with consequences on fertility. Different animal models of exposure to glyphosate or glyphosate-based herbicides (GBHs) have shown that the effects on the female reproductive tract may be related to the potential and/or mechanisms of actions of an endocrine-disrupting compound. Studies have also demonstrated that the exposure to GBHs alters the development and differentiation of ovarian follicles and uterus, affecting fertility when animals are exposed before puberty. In addition, exposure to GBHs during gestation could alter the development of the offspring (F1 and F2). The main mechanism described associated with the endocrine-disrupting effect of GBHs is the modulation of estrogen receptors and molecules involved in the estrogenic pathways. This review summarizes the endocrine-disrupting effects of exposure to glyphosate and GBHs at low or “environmentally relevant” doses in the female reproductive tissues. Data suggesting that, at low doses, GBHs may have adverse effects on the female reproductive tract fertility are discussed. FULL TEXT

Griffin et al., 1997

Griffin, R. J., Godfrey, V. B., Kim, Y. C., & Burka, L. T.; “Sex-dependent differences in the disposition of 2,4-dichlorophenoxyacetic acid in Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters;” Drug Metabolism and Disposition, 1997, 25(9), 1065-1071.


2,4-Dichlorophenoxyacetic acid (2,4-D), a widely used broadleaf herbicide, is under investigation in a study of peroxisome proliferators. To supplement that study, male and female rats, mice, and hamsters were dosed with 14C-2,4-D orally at 5 and 200 mg/kg and tissue distributions were determined. Blood, liver, kidney, muscle, skin, fat, brain, testes, and ovaries were examined. At early time points tissues from female rats consistently contained higher amounts of radioactivity than did corresponding tissues from males (up to 9 times). By 72 hr, tissue levels were equivalent and males and females had excreted equal amounts of radioactivity. This sex difference was absent in mice. In hamsters, males had higher tissue levels than females. Taurine, glycine, and glucuronide conjugates of 2,4-D were excreted along with parent. Metabolite profiles differed between species qualitatively and quantitatively; however, differences between sexes were minimal. Plasma elimination curves were generated in male and female rats after iv and oral administration. Kinetic analysis revealed significant differences in elimination and exposure parameters consistent with a greater ability to clear 2,4-D by male rats relative to females. This suggests that at equivalent doses, female rats are exposed to higher concentrations of 2,4-D for a longer time than males and may be more susceptible to 2,4-D-induced toxicity. These sex-dependent variations in the clearance of 2,4-D in rats and hamsters may indicate a need for sex-specific models to accurately assess human health risks. FULL TEXT

Saldana et al., 2007

Saldana, T. M., Basso, O., Hoppin, J. A., Baird, D. D., Knott, C., Blair, A., Alavanja, M. C., & Sandler, D. P.; “Pesticide exposure and self-reported gestational diabetes mellitus in the Agricultural Health Study;” Diabetes Care, 2007, 30(3), 529-534; DOI: 10.2337/dc06-1832.


OBJECTIVE: To examine the association between pesticide use during pregnancy and gestational diabetes mellitus (GDM) among wives of licensed pesticide applicators.

RESEARCH DESIGN AND METHODS: Using data from the Agricultural Health Study (AHS), we estimated the association between self-reported pesticide-related activities during the first trimester of the most recent pregnancy and GDM among 11,273 women whose pregnancy occurred within 25 years of enrollment.

RESULTS: A total of 506 (4.5%) women reported having had GDM. Women who reported agricultural pesticide exposure (mixing or applying pesticides to crops or repairing pesticide application equipment) during pregnancy were more likely to report GDM (odds ratio [OR] 2.2 [95% CI 1.5-3.3]). We saw no association between residential pesticide exposure (applying pesticides in the home and garden during pregnancy) and GDM (1.0 [0.8-1.3]). Among women who reported agricultural exposure during pregnancy, risk of GDM was associated with ever-use of four herbicides (2,4,5-T; 2,4,5-TP; atrazine; or butylate) and three insecticides (diazinon, phorate, or carbofuran).

CONCLUSIONS: These findings suggest that activities involving exposure to agricultural pesticides during the first trimester of pregnancy may increase the risk of GDM.


Chiu, 2017

Chiu, Y. H.,”Pesticide Residues in Fruits and Vegetables: Assessment and Their Associations With Reproductive Health Outcomes;” Dissertation at Harvard Universiry, (Doctor of Science in Nutrition and Epidemiology); 2017.


According to the Dietary Guideline, consumption of fruits and vegetables (FVs) are recommended throughout the lifespan, including during pregnancy. FVs, on the other hand, can serve as a vehicle of exposure to pesticide residues. In the US, Environmental Protection Agency (EPA) is responsible for regulating pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act and the Food Quality Protection Act. While majority of the produce sampled through the US Department of Agriculture had residues below the EPA limits, there is a growing concern whether chronic exposure to these pesticide residues may have adverse health effects, especially among susceptible populations such as pregnant women. Yet, such research is scarce. This dissertation focuses on the assessment of pesticide residues in FVs and evaluates their associations with pregnancy outcomes.

We previously have developed the Pesticide Residue Burden Score (PRBS) based on selfreported diet and national surveillance data on food pesticide residues to characterize dietary exposure over the past year. In Chapter 1, we evaluated the association of the PRBS with urinary pesticide metabolites in the Environment and Reproductive Health (EARTH) Study. We found intake of high pesticide residues FVs was positively associated with urinary concentrations of pesticide biomarkers, suggesting that PRBS can characterize dietary exposure to select pesticides.

In Chapter 2, we assessed the relation between preconception intake of high and low FVs and assisted reproductive technology outcomes in EARTH study. We found that intake of high pesticide residues FVs was associated with lower probability of clinical pregnancy and live birth, while intake of low pesticide residue FVs had the opposite relations among women undergoing infertility treatment. This is the first report of such relation in humans.

In Chapter 3, we examine the association between maternal intake of high and low pesticide residue FVs with birth outcomes in a pre-birth cohort. We found that maternal intake of high pesticide residue FVs during the first trimester was associated with higher risks of small-for-gestational-age among white women, while these exposures was associated with large-for-gestational-age among nonwhite women.

In conclusion, this work demonstrated the usefulness of PRBS in assessing pesticide residue intake through FVs. Using this method, these studies suggest exposure to pesticide residues may adversely affect pregnancy and birth outcomes.


Ait-Bali et al., 2020

Ait-Bali, Y., Ba-M’hamed, S., Gambarotta, G., Sassoe-Pognetto, M., Giustetto, M., & Bennis, M.; “Pre- and postnatal exposure to glyphosate-based herbicide causes behavioral and cognitive impairments in adult mice: evidence of cortical ad hippocampal dysfunction;” Archives of Toxicology, 2020; DOI: 10.1007/s00204-020-02677-7.


Glyphosate-based herbicides (GBH) are the most widely used pesticides worldwide. Despite considerable progress in describing the neurotoxic potential of GBH, the harmful effects on brain cytoarchitecture and behavior are still unclear. Here, we addressed the developmental impact of GBH by exposing female mice to 250 or 500 mg/kg doses of GBH during both pregnancy and lactation and then examined the downstream effects at the behavioral, neurochemical and molecular levels. We show that pre- and neonatal exposure to GBH impairs fertility and reproduction parameters as well as maternal behavior of exposed mothers. In offspring, GBH was responsible for a global delay in innate reflexes and a deficit in motor development. At the adult age, exposed animals showed a decrease of locomotor activity, sociability, learning and short- and long-term memory associated with alterations of cholinergic and dopaminergic systems. Furthermore, GBH-activated microglia and astrocytes, sign of neuroinflammation event in the medial prefrontal cortex and hippocampus. At the molecular level, a down-regulation of brain-derived neurotrophic factor (BDNF) expression and an up-regulation of tyrosine-related kinase receptor (TrkB), NR1 subunit of NMDA receptor as well as tumor necrosis factor alpha (TNFalpha) were found in the brain of GBH-exposed mice. The present work demonstrates that GBH induces numerous behavioral and cognitive abnormalities closely associated with significant histological, neurochemical and molecular impairments. It also raises fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during developmental periods of central nervous system. FULL TEXT