Heindel, 2006
Heindel JJ, “Role of exposure to environmental chemicals in the developmental basis of reproductive disease and dysfunction,” Seminars in Reproductive Medicine, 2006, 24:3.
ABSTRACT: There is a paradigm shift in science at present that indicates that the onset of many diseases, including reproductive diseases and dysfunctions, are already programmed in utero or in the early postnatal period. This new field is called the developmental basis of health and disease. Although focus has been on the role of in utero nutrition and its effects on subsequent adult-onset diseases, it is clear that exposure to environmental stressors/toxicants in utero or during early development can also increase susceptibility to disease later in life. The mechanism for this in utero and early developmental effect is thought to be altered epigenetic control of gene expression, which alters developmental programming and results in a tissue that may appear normal but is functionally compromised. Although this concept is still a hypothesis, this review addresses the current state of data relating to proving its importance and role in reproductive diseases. If the developmental basis of disease is shown to be true, then examination of the etiology of disease and prevention and intervention strategies will need to be modified to fit the new paradigm.
Gasnier et al., 2009.
Gasnier C, Dumont C, Benachour N, Clair E, Chagnon MC, Séralini GE, “Glyphosate-based herbicides are toxic and endocrine disruptors in human cell lines,” Toxicology, 2009, 262:3. DOI: 10.1016/j.tox.2009.06.006.
ABSTRACT: 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.
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., 2002b
Garry VF, Harkins ME, Erickson LL, Long-Simpson LK, Holland SE, Burroughs BL, “Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA,” Environmental Health Perspectives, 2002, 110: Supplemental 3.
ABSTRACT:
We previously demonstrated that the frequency of birth defects among children of residents of the Red River Valley (RRV), Minnesota, USA, was significantly higher than in other major agricultural regions of the state during the years 1989-1991, with children born to male pesticide applicators having the highest risk. The present, smaller cross-sectional study of 695 families and 1,532 children, conducted during 1997-1998, provides a more detailed examination of reproductive health outcomes in farm families ascertained from parent-reported birth defects. In the present study, in the first year of life, the birth defect rate was 31.3 births per 1,000, with 83% of the total reported birth defects confirmed by medical records. Inclusion of children identified with birth or developmental disorders within the first 3 years of life and later led to a rate of 47.0 per 1,000 (72 children from 1,532 live births). Conceptions in spring resulted in significantly more children with birth defects than found in any other season (7.6 vs. 3.7%). Twelve families had more than one child with a birth defect (n = 28 children). Forty-two percent of the children from families with recurrent birth defects were conceived in spring, a significantly higher rate than that for any other season. Three families in the kinships defined contributed a first-degree relative other than a sibling with the same or similar birth defect, consistent with a Mendelian inheritance pattern. The remaining nine families did not follow a Mendelian inheritance pattern. The sex ratio of children with birth defects born to applicator families shows a male predominance (1.75 to 1) across specific pesticide class use and exposure categories exclusive of fungicides. In the fungicide exposure category, normal female births significantly exceed male births (1.25 to 1). Similarly, the proportion of male to female children with birth defects is significantly lower (0.57 to 1; p = 0.02). Adverse neurologic and neurobehavioral developmental effects clustered among the children born to applicators of the fumigant phosphine (odds ratio [OR] = 2.48; confidence interval [CI], 1.2-5.1). Use of the herbicide glyphosate yielded an OR of 3.6 (CI, 1.3-9.6) in the neurobehavioral category. Finally, these studies point out that (a) herbicides applied in the spring may be a factor in the birth defects observed and (b) fungicides can be a significant factor in the determination of sex of the children of the families of the RRV. Thus, two distinct classes of pesticides seem to have adverse effects on different reproductive outcomes. Biologically based confirmatory studies are needed. 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. FULL TEXT
Garry et al., 2003
Garry VF, Holland SE, Erickson LL, Burroughs BL, “Male reproductive hormones and thyroid function in pesticide applicators in the Red River Valley of Minnesota,” Journal of Toxicology and Environmental Health – Part A, 2003, 66:11.
ABSTRACT: In the present effort, 144 pesticide applicators and 49 urban control subjects who reported no chronic disease were studied. Applicators provided records of the season’s pesticides used by product, volumes, dates, and methods of application. Blood specimens for examination of hormone levels were obtained in summer and fall. In the herbicide-only applicator group, significant increases in testosterone levels in fall compared to summer and also elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the fall were noted. With respect to fungicide use, in an earlier cross-sectional epidemiologic study, data demonstrated that historic fungicide use was associated with a significant alteration of the sex ratio of children borne to applicators. As before, among current study subjects it was noted that historic fungicide use was associated with increased numbers of girls being born. Lower mean total testosterone concentrations by quartile were also correlated with increased numbers of live-born female infants. A downward summer to fall seasonal shift in thyroid-stimulating hormone (TSH) concentrations occurred among applicators but not among controls. Farmers who had aerial application of fungicides to their land in the current season showed a significant shift in TSH values (from 1.75 to 1.11 mU/L). Subclinical hypothyroidism was noted in 5/144 applicators (TSH values >4.5 mU/L), but not in urban control subjects. Based on current and past studies, it was concluded that, in addition to pesticide exposure, individual susceptibility and perhaps economic factors may play a supporting role in the reported results.
Defarge et al., 2016
Defarge N, Takács E, Lozano VL, Mesnage R, Spiroux de Vendômois J, Séralini GE, Székács A, “Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels,” International Journal of Environmental Research and Public Health, 2016, 13:3.
ABSTRACT:
Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18-2000 times for co-formulants, 8-141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine-POEA and alkyl polyglucoside-APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone. FULL TEXT
Collotta et al., 2013
Collotta, M, Bertazzi, PA, Bollati, V, “Epigenetics and pesticides,” Toxicology, 2013, 307, DOI: 10.1016/j.tox.2013.01.017.
ABSTRACT: Pesticides, a wide class of environmental contaminants, may cause both acute and delayed health effects in exposed subjects. These effects can range from simple irritation of the skin and eyes to more severe effects such as affecting the nervous system, the reproductive system and cancer. The molecular mechanisms underlying such effects are still under investigation. Epigenetics is the study of heritable changes in gene expression that occur without a change in the DNA sequence. Several epigenetic mechanisms, including DNA methylation, histone modifications and microRNA expression, can be triggered by environmental factors.We review current evidences indicating that epigenetic modifications may mediate pesticide effects on human health. In vitro, animal, and human investigations have identified several classes of pesticides that modify epigenetic marks, including endocrine disruptors, persistent organic pollutants, arsenic, several herbicides and insecticides. Several investigations have examined the effects of environmental exposures and epigenetic markers, and identified toxicants that modify epigenetic states. These modifications are similar to the ones found in pathological tissue samples. In spite of the current limitations, available evidence supports the concept that epigenetics holds substantial potential for furthering our understanding of the molecular mechanisms of pesticides health effects, as well as for predicting health-related risks due to conditions of environmental exposure and individual susceptibility. FULL TEXT
Conrad et al., 2017
Conrad A, Schröter-Kermani C, Hoppe HW, Rüther M, Pieper S, Kolossa-Gehring M, “Glyphosate in German adults – Time trend (2001 to 2015) of human exposure to a widely used herbicide,” International Journal of Hygiene and Environmental Health, 2017, 220:1, doi: 10.1016/j.ijheh.2016.09.016.
ABSTRACT:
The broadband herbicide glyphosate (N-[phosphonomethyl]-glycine) and its main metabolite aminomethylphosphonic acid (AMPA) were analyzed by GC-MS-MS in 24h-urine samples cryo-archived by the German Environmental Specimen Bank (ESB). Samples collected in 2001, 2003, 2005, 2007, 2009, 2011, 2012, 2013, 2014, and 2015 were chosen for this retrospective analysis. All urine samples had been provided by 20 to 29 years old individuals living in Greifswald, a city in north-eastern Germany. Out of the 399 analyzed urine samples, 127 (=31.8%) contained glyphosate concentrations at or above the limit of quantification (LOQ) of 0.1μg/L. For AMPA this was the case for 160 (=40.1%) samples. The fraction of glyphosate levels at or above LOQ peaked in 2012 (57.5%) and 2013 (56.4%) after having discontinuously increased from 10.0% in 2001. Quantification rates were lower again in 2014 and 2015 with 32.5% and 40.0%, respectively. The overall trend for quantifiable AMPA levels was similar. Glyphosate and AMPA concentrations in urine were statistically significantly correlated (spearman rank correlation coefficient=0.506, p≤0.001). Urinary glyphosate and AMPA levels tended to be higher in males. The possible reduction in exposure since 2013 indicated by ESB data may be due to changes in glyphosate application in agricultural practice. The ESB will continue monitoring internal exposures to glyphosate and AMPA for following up the time trend, elucidating inter-individual differences, and contributing to the ongoing debate on the further regulation of glyphosate-based pesticides. FULL TEXT
Cohn et al., 2007
Cohn BA, Wolff MS, Cirillo PM, Sholtz RI, “DDT and breast cancer in young women: new data on the significance of age at exposure,” Environmental Health Perspectives, 2007, 115:10.
ABSTRACT:
BACKGROUND: Previous studies of DDT and breast cancer assessed exposure later in life when the breast may not have been vulnerable, after most DDT had been eliminated, and after DDT had been banned.
OBJECTIVES: We investigated whether DDT exposure in young women during the period of peak DDT use predicts breast cancer.
METHODS: We conducted a prospective, nested case-control study with a median time to diagnosis of 17 years using blood samples obtained from young women during 1959-1967. Subjects were members of the Child Health and Development Studies, Oakland, California, who provided blood samples 1-3 days after giving birth (mean age, 26 years). Cases (n = 129) developed breast cancer before the age of 50 years. Controls (n = 129) were matched to cases on birth year. Serum was assayed for p,p’-DDT, the active ingredient of DDT; o,p’-DDT, a low concentration contaminant; and p,p’-DDE, the most abundant p,p’-DDT metabolite.
RESULTS: High levels of serum p,p’-DDT predicted a statistically significant 5-fold increased risk of breast cancer among women who were born after 1931. These women were under 14 years of age in 1945, when DDT came into widespread use, and mostly under 20 years as DDT use peaked. Women who were not exposed to p,p’-DDT before 14 years of age showed no association between p,p’-DDT and breast cancer (p = 0.02 for difference by age).
CONCLUSIONS: Exposure to p,p’-DDT early in life may increase breast cancer risk. Many U.S. women heavily exposed to DDT in childhood have not yet reached 50 years of age. The public health significance of DDT exposure in early life may be large. FULL TEXT