Cohn et al., 2015
Cohn BA, La Merrill M, Krigbaum NY, Yeh G, Park JS, Zimmermann L, Cirillo PM, “DDT Exposure in Utero and Breast Cancer,” Journal of Clinical Endocrinology and Metabolism, 2015, 100:8, doi: 10.1210/jc.2015-1841.
ABSTRACT:
CONTEXT: Currently no direct evidence links in utero dichlorodiphenyltrichloroethane (DDT) exposure to human breast cancer. However, in utero exposure to another xenoestrogen, diethylstilbestrol, predicts an increased breast cancer risk. If this finding extends to DDT, it could have far-reaching consequences. Many women were heavily exposed in utero during widespread DDT use in the 1960s. They are now reaching the age of heightened breast cancer risk. DDT exposure persists and use continues in Africa and Asia without clear knowledge of the consequences for the next generation.
HYPOTHESIS: In utero exposure to DDT is associated with an increased risk of breast cancer.
DESIGN: This was a case-control study nested in a prospective 54-year follow-up of 9300 daughters in the Child Health and Development Studies pregnancy cohort (n = 118 breast cancer cases, diagnosed by age 52 y and 354 controls matched on birth year).
SETTING AND PARTICIPANTS: Kaiser Foundation Health Plan members who received obstetric care in Alameda County, California, from 1959 to 1967, and their adult daughters participated in the study.
MAIN OUTCOME MEASURE: Daughters’ breast cancer diagnosed by age 52 years as of 2012 was measured.
RESULTS: Maternal o,p’-DDT predicted daughters’ breast cancer (odds ratio fourth quartile vs first = 3.7, 95% confidence interval 1.5-9.0). Mothers’ lipids, weight, race, age, and breast cancer history did not explain the findings.
CONCLUSIONS: This prospective human study links measured DDT exposure in utero to risk of breast cancer. Experimental studies are essential to confirm results and discover causal mechanisms. Findings support classification of DDT as an endocrine disruptor, a predictor of breast cancer, and a marker of high risk. FULL TEXT
Clair et al., 2012
Clair E, Mesnage R, Travert C, Séralini GÉ, “A glyphosate-based herbicide induces necrosis and apoptosis in mature rat testicular cells in vitro, and testosterone decrease at lower levels,” Toxicology In Vitro, 2012, 26:2, doi: 10.1016/j.tiv.2011.12.009.
ABSTRACT: The major herbicide used worldwide, Roundup, is a glyphosate-based pesticide with adjuvants. Glyphosate, its active ingredient in plants and its main metabolite (AMPA) are among the first contaminants of surface waters. Roundup is being used increasingly in particular on genetically modified plants grown for food and feed that contain its residues. Here we tested glyphosate and its formulation on mature rat fresh testicular cells from 1 to 10000ppm, thus from the range in some human urine and in environment to agricultural levels. We show that from 1 to 48h of Roundup exposure Leydig cells are damaged. Within 24-48h this formulation is also toxic on the other cells, mainly by necrosis, by contrast to glyphosate alone which is essentially toxic on Sertoli cells. Later, it also induces apoptosis at higher doses in germ cells and in Sertoli/germ cells co-cultures. At lower non toxic concentrations of Roundup and glyphosate (1ppm), the main endocrine disruption is a testosterone decrease by 35%. The pesticide has thus an endocrine impact at very low environmental doses, but only a high contamination appears to provoke an acute rat testicular toxicity. This does not anticipate the chronic toxicity which is insufficiently tested, and only with glyphosate in regulatory tests.
CDC, 2013
Centers for Disease Control, “Fourth national report on human exposure to environmental chemicals: Updated tables, September 2012,” 2013, U.S. Dept. Health Human Services, available at: https://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Sep2012.pdf
CDC, 2015
Centers for Disease Control, “Fourth national report on human exposure to environmental chemicals: Updated tables, February 2015,” 2015, U.S. Dept. Health Human Services, available at: https://www.cdc.gov/biomonitoring/pdf/fourthreport_updatedtables_feb2015.pdf
Castillo-Fernandez et al., 2014
Castillo-Fernandez JE, Spector TD, Bell JT, “Epigenetics of discordant monozygotic twins: implications for disease,” Genome Medicine, 2014, 6:7, doi: 10.1186/s13073-014-0060-z.
ABSTRACT:
Monozygotic (MZ) twins share nearly all of their genetic variants and many similar environments before and after birth. However, they can also show phenotypic discordance for a wide range of traits. Differences at the epigenetic level may account for such discordances. It is well established that epigenetic states can contribute to phenotypic variation, including disease. Epigenetic states are dynamic and potentially reversible marks involved in gene regulation, which can be influenced by genetics, environment, and stochastic events. Here, we review advances in epigenetic studies of discordant MZ twins, focusing on disease. The study of epigenetics and disease using discordant MZ twins offers the opportunity to control for many potential confounders encountered in general population studies, such as differences in genetic background, early-life environmental exposure, age, gender, and cohort effects. Recently, analysis of disease-discordant MZ twins has been successfully used to study epigenetic mechanisms in aging, cancer, autoimmune disease, psychiatric, neurological, and multiple other traits. Epigenetic aberrations have been found in a range of phenotypes, and challenges have been identified, including sampling time, tissue specificity, validation, and replication. The results have relevance for personalized medicine approaches, including the identification of prognostic, diagnostic, and therapeutic targets. The findings also help to identify epigenetic markers of environmental risk and molecular mechanisms involved in disease and disease progression, which have implications both for understanding disease and for future medical research. FULL TEXT
Carmichael et al., 2016
Carmichael SL, Yang W, Roberts E, Kegley SE, Brown TJ, English PB, Lammer EJ, Shaw GM, “Residential agricultural pesticide exposures and risks of selected birth defects among offspring in the San Joaquin Valley of California,” Birth Defects Research Part A: Clinical and Molecular Teratology, 2016, 106:1, doi: 10.1002/bdra.23459.
ABSTRACT:
BACKGROUND: We examined associations of birth defects with residential proximity to commercial agricultural pesticide applications in California. Subjects included 367 cases representing five types of birth defects and 785 nonmalformed controls born 1997 to 2006.
METHODS:Associations with any versus no exposure to physicochemical groups of pesticides and specific chemicals were assessed using logistic regression adjusted for covariates. Overall, 46% of cases and 38% of controls were classified as exposed to pesticides within a 500 m radius of mother’s address during a 3-month periconceptional window.
RESULTS:We estimated odds ratios (ORs) for 85 groups and 95 chemicals with five or more exposed cases and control mothers. Ninety-five percent confidence intervals (CI) excluded 1.0 for 11 ORs for groups and 22 ORs for chemicals, ranging from 1.9 to 3.1 for groups and 1.8 to 4.9 for chemicals except for two that were <1 (noted below).
CONCLUSION:For groups, these ORs were for anotia/microtia (n = 95 cases) and dichlorophenoxy acids/esters and neonicotinoids; anorectal atresia/stenosis (n = 77) and alcohol/ethers and organophosphates (these ORs were < 1.0); transverse limb deficiencies (n = 59) and dichlorophenoxy acids/esters, petroleum derivatives, and triazines; and craniosynostosis (n = 79) and alcohol/ethers, avermectins, neonicotinoids, and organophosphates. For chemicals, ORs were: anotia/microtia and five pesticides from the groups dichlorophenoxy acids/esters, copper-containing compounds, neonicotinoids, organophosphates, and triazines; transverse limb deficiency and six pesticides – oxyfluorfen and pesticides from the groups copper-containing compounds, 2,6-dinitroanilines, neonicotinoids, petroleum derivatives and polyalkyloxy compounds; craniosynostosis and 10 pesticides – oxyfluorfen and pesticides from the groups alcohol/ethers, avermectins, n-methyl-carbamates, neonicotinoids, ogranophosphates (two chemicals), polyalkyloxy compounds (two chemicals), and pyrethroids; and congenital diaphragmatic hernia (n = 62) and a copper-containing compound. 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.
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.
Adams et al., 2016
Adams, A, Friesen, M, Olson, A, Gerona, R. “Biomonitoring of glyphosate across the United States in urine and tap water using high-fidelity LC-MS/MS method,” 2016. Poster presentation, access at: http://hh-ra.org/wp-content/uploads/2017/02/APAMT-Poster-Gerona.pdf.
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. FULL TEXT