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      Glyphosate exposure in pregnancy and shortened gestational length: a prospective Indiana birth cohort study

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          Abstract

          Background

          Glyphosate (GLY) is the most heavily used herbicide worldwide but the extent of exposure in human pregnancy remains unknown. Its residues are found in the environment, major crops, and food items that humans, including pregnant women, consume daily. Since GLY exposure in pregnancy may also increase fetal exposure risk, we designed a birth-cohort study to determine exposure frequency, potential exposure pathways, and associations with fetal growth indicators and pregnancy length.

          Method

          Urine and residential drinking water samples were obtained from 71 women with singleton pregnancies living in Central Indiana while they received routine prenatal care. GLY measurements were performed using liquid chromatography-tandem mass spectrometry. Demographic and survey information relating to food and water consumption, stress, and residence were obtained by questionnaire. Maternal risk factors and neonatal outcomes were abstracted from medical records. Correlation analyses were used to assess relationships of urine GLY levels with fetal growth indicators and gestational length.

          Results

          The mean age of participants was 29 years, and the majority were Caucasian. Ninety three percent of the pregnant women had GLY levels above the limit of detection (0.1 ng/mL). Mean urinary GLY was 3.40 ng/mL (range 0.5–7.20 ng/mL). Higher GLY levels were found in women who lived in rural areas ( p = 0.02), and in those who consumed > 24 oz. of caffeinated beverages per day ( p = 0.004). None of the drinking water samples had detectable GLY levels. We observed no correlations with fetal growth indicators such as birth weight percentile and head circumference. However, higher GLY urine levels were significantly correlated with shortened gestational lengths (r = − 0.28, p = 0.02).

          Conclusions

          This is the first study of GLY exposure in US pregnant women using urine specimens as a direct measure of exposure. We found that > 90% of pregnant women had detectable GLY levels and that these levels correlated significantly with shortened pregnancy lengths. Although our study cohort was small and regional and had limited racial/ethnic diversity, it provides direct evidence of maternal GLY exposure and a significant correlation with shortened pregnancy. Further investigations in a more geographically and racially diverse cohort would be necessary before these findings could be generalized.

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          Most cited references39

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          Fetal origins of coronary heart disease.

          The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease. Animal studies have shown that undernutrition before birth programmes persisting changes in a range of metabolic, physiological, and structural parameters. Studies in humans have shown that men and women whose birth weights were at the lower end of the normal range, who were thin or short at birth, or who were small in relation to placental size have increased rates of coronary heart disease. We are beginning to understand something of the mechanisms underlying these associations. The programming of blood pressure, insulin responses to glucose, cholesterol metabolism, blood coagulation, and hormonal settings are all areas of active research.
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            Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement

            The broad-spectrum herbicide glyphosate (common trade name “Roundup”) was first sold to farmers in 1974. Since the late 1970s, the volume of glyphosate-based herbicides (GBHs) applied has increased approximately 100-fold. Further increases in the volume applied are likely due to more and higher rates of application in response to the widespread emergence of glyphosate-resistant weeds and new, pre-harvest, dessicant use patterns. GBHs were developed to replace or reduce reliance on herbicides causing well-documented problems associated with drift and crop damage, slipping efficacy, and human health risks. Initial industry toxicity testing suggested that GBHs posed relatively low risks to non-target species, including mammals, leading regulatory authorities worldwide to set high acceptable exposure limits. To accommodate changes in GBH use patterns associated with genetically engineered, herbicide-tolerant crops, regulators have dramatically increased tolerance levels in maize, oilseed (soybeans and canola), and alfalfa crops and related livestock feeds. Animal and epidemiology studies published in the last decade, however, point to the need for a fresh look at glyphosate toxicity. Furthermore, the World Health Organization’s International Agency for Research on Cancer recently concluded that glyphosate is “probably carcinogenic to humans.” In response to changing GBH use patterns and advances in scientific understanding of their potential hazards, we have produced a Statement of Concern drawing on emerging science relevant to the safety of GBHs. Our Statement of Concern considers current published literature describing GBH uses, mechanisms of action, toxicity in laboratory animals, and epidemiological studies. It also examines the derivation of current human safety standards. We conclude that: (1) GBHs are the most heavily applied herbicide in the world and usage continues to rise; (2) Worldwide, GBHs often contaminate drinking water sources, precipitation, and air, especially in agricultural regions; (3) The half-life of glyphosate in water and soil is longer than previously recognized; (4) Glyphosate and its metabolites are widely present in the global soybean supply; (5) Human exposures to GBHs are rising; (6) Glyphosate is now authoritatively classified as a probable human carcinogen; (7) Regulatory estimates of tolerable daily intakes for glyphosate in the United States and European Union are based on outdated science. We offer a series of recommendations related to the need for new investments in epidemiological studies, biomonitoring, and toxicology studies that draw on the principles of endocrinology to determine whether the effects of GBHs are due to endocrine disrupting activities. We suggest that common commercial formulations of GBHs should be prioritized for inclusion in government-led toxicology testing programs such as the U.S. National Toxicology Program, as well as for biomonitoring as conducted by the U.S. Centers for Disease Control and Prevention.
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              Glyphosate-based herbicides are toxic and endocrine disruptors in human cell lines.

              Glyphosate-based herbicides are the most widely used across the world; they are commercialized in different formulations. Their residues are frequent pollutants in the environment. In addition, these herbicides are spread on most eaten transgenic plants, modified to tolerate high levels of these compounds in their cells. Up to 400 ppm of their residues are accepted in some feed. We exposed human liver HepG2 cells, a well-known model to study xenobiotic toxicity, to four different formulations and to glyphosate, which is usually tested alone in chronic in vivo regulatory studies. We measured cytotoxicity with three assays (Alamar Blue, MTT, ToxiLight), plus genotoxicity (comet assay), anti-estrogenic (on ERalpha, ERbeta) and anti-androgenic effects (on AR) using gene reporter tests. We also checked androgen to estrogen conversion by aromatase activity and mRNA. All parameters were disrupted at sub-agricultural doses with all formulations within 24h. These effects were more dependent on the formulation than on the glyphosate concentration. First, we observed a human cell endocrine disruption from 0.5 ppm on the androgen receptor in MDA-MB453-kb2 cells for the most active formulation (R400), then from 2 ppm the transcriptional activities on both estrogen receptors were also inhibited on HepG2. Aromatase transcription and activity were disrupted from 10 ppm. Cytotoxic effects started at 10 ppm with Alamar Blue assay (the most sensitive), and DNA damages at 5 ppm. A real cell impact of glyphosate-based herbicides residues in food, feed or in the environment has thus to be considered, and their classifications as carcinogens/mutagens/reprotoxics is discussed.
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                Author and article information

                Contributors
                parvezs@iu.edu
                roy.gerona@ucsf.edu
                proctorc@iu.edu
                matthew.friesen@ucsf.edu
                jlashby@iupui.edu
                jireiter@iu.edu
                ziliu@iu.edu
                paul.winchester@franciscanalliance.org
                Journal
                Environ Health
                Environ Health
                Environmental Health
                BioMed Central (London )
                1476-069X
                9 March 2018
                9 March 2018
                2018
                : 17
                : 23
                Affiliations
                [1 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Environmental Health Science, , Indiana University Fairbanks School of Public Health, ; 1050 Wishard Boulevard, Indianapolis, IN 46202 USA
                [2 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Gynecology, Obstetrics and Reproductive Sciences, , University of California San Francisco, ; 505 Parnassus Ave Moffitt Hospital M879B, San Francisco, CA 94143 USA
                [3 ]Franciscan Health, 8111 S Emerson Avenue, Indianapolis, IN 46237 USA
                [4 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Neonatal-Perinatal Medicine, Riley Children’s Hospital, , Indiana University School of Medicine, ; 699 Riley Hospital Dr RR 208, Indianapolis, IN 46202 USA
                [5 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Obstetrics and Gynecology, , Indiana University School of Medicine, ; 1044 W. Walnut, R4 035, Indianapolis, IN 46202 USA
                [6 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Department of Biostatistics, , Indiana University Fairbanks School of Public Health, ; 410 W. Tenth St., Suite 3000, Indianapolis, IN 46202 USA
                Author information
                http://orcid.org/0000-0001-5696-056X
                Article
                367
                10.1186/s12940-018-0367-0
                5844093
                29519238
                ff4afb5a-c961-4917-a386-7f0cbc1ce64e
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 3 September 2017
                : 20 February 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100006975, Indiana Clinical and Translational Sciences Institute;
                Award ID: UL1TR001108
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Public health
                glyphosate,roundup,herbicides,pregnancy,exposure assessment,gestational length,birth weight percentile,head circumference,birth outcomes,caffeine

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