Anway, Matthew D., Cupp, Andrea S., Uzumcu, Mehmet, and Skinner, Michael K., “Transgenerational Actions of Endocrine Disruptors and Male Fertility,” Science, 2005, 308:5727, DOI: 10.1126/SCIENCE.1108190.
Transgenerational effects of environmental toxins require either a chromosomal or epigenetic alteration in the germ line. Transient exposure of a gestating female rat during the period of gonadal sex determination to the endocrine disruptors vinclozolin (an antiandrogenic compound) or methoxychlor (an estrogenic compound) induced an adult FULL TEXTin the F1 generation of decreased spermatogenic capacity (cell number and viability) and increased incidence of male infertility. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined (that is, F1 to F4). The effects on reproduction correlate with altered DNA patterns in the germ line. The ability of an environmental factor (for example, endocrine disruptor) to reprogram the germ line and to promote a transgenerational disease state has significant implications for evolutionary biology and disease .
Koureas M, Tsakalof A, Tsatsakis A, Hadjichristodoulou C., “Systematic review of biomonitoring studies to determine the association between exposure to organophosphorus and pyrethroidand human health outcomes,” Toxicology Letters, 2012, 210:2, DOI: 10.1016/j.toxlet.2011.10.007.
For the appropriate protection of human health it is necessary to accurately estimate the health effects of human exposure to toxic compounds. In the present review,on the health effects of human exposure to organophosphorus (OP) and pyrethroid (PYR) insecticides have been critically assessed. This review is focused on studies where the exposure assessment was based on quantification of specific biomarkers in urine or plasma. The 49 studies reviewed used different epidemiological approaches and analytical methods as well as different exposure assessment methodologies. With regard to OP pesticides, the studies reviewed suggested negative effects of prenatal exposure to these pesticides on neurodevelopment and male reproduction. Neurologic effects on adults, DNA damage and adverse birth outcomes were also associated with exposure to OP pesticides. With regard to exposure to PYR pesticides, there are currently few studies investigating the adverse health outcomes due to these pesticides. The effects studied in relation to PYR exposure were mainly male reproductive effects (sperm quality, sperm DNA damage and reproductive hormone disorders). Studies’ findings provided evidence to support the hypothesis that PYR exposure is adversely associated with effects on the male reproductive system. The validity of these epidemiological studies is strongly enhanced by exposure assessment based on biomarker quantification. However, for valid and reliable results and conclusions, attention should also be focused on the validity of the analytical methods used, study designs and the measured toxicants characteristics.
Lopes FM, Varela Junior AS, Corcini CD, da Silva AC, Guazzelli VG, Tavares G, da Rosa CE, “Effect of glyphosate on the sperm quality of zebrafish Danio rerio,” Aquatic Toxicology, 2014, 155, DOI: 10.1016/j.aquatox.2014.07.006.
Glyphosate is a systemic, non-selective herbicide widely used in agriculture worldwide. It acts as an inhibitor of the5-enolpyruvylshikimate-3-phosphate synthase by interrupting the synthesis of essential aromatic . This pathway is not present in animals, although some studies have shown that the herbicide glyphosate can affect fish reproduction. In this study, the effect of glyphosate on sperm quality of the fish Danio rerio was investigated after 24 and 96 h of exposure at concentrations of 5mg/L and 10mg/L. The spermatic cell concentration, sperm motility and motility period were measured employing conventional microscopy. The mitochondrial functionality, membrane integrity and DNA integrity were measured by fluorescence microscopy using specific probes. No significant differences in sperm concentration were observed; however, sperm motility and the motility period were reduced after exposure to both glyphosate concentrations during both exposure periods. The mitochondrial functionality and membrane and DNA integrity were also reduced at the highest concentration during both exposure periods. The results showed that glyphosate can induce harmful effects on reproductive parameters in D. rerio and that this change would reduce the fertility rate of these animals.
Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK, “Pesticide and insect repellent mixture (permethrin and DEET) inducestransgenerational 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 FULL TEXTepimutations 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.
Mohan Manikkam, Rebecca Tracey, Carlos Guerrero-Bosagna, Michael K. Skinner , “Dioxin (TCDD) InducesTransgenerational Inheritance of Adult Onset Disease and Sperm Epimutations,” PLoS ONE, 2012, 7:9, DOI: 10.1371/journal.pone.0046249.
Environmental compounds can promote epigenetic transgenerational inheritance of adult-onset disease in subsequent generations following ancestral exposure during fetal gonadal sex determination. The current study examined the ability of dioxin (2,3,7,8-tetrachlorodibenzo[p]dioxin, TCDD) to promote epigenetic transgenerational inheritance of disease and DNA FULL TEXTepimutations in sperm. Gestating F0 generation females were exposed to dioxin during fetal day 8 to 14 and adult-onset disease was evaluated in F1 and F3 generation rats. The incidences of total disease and multiple disease increased in F1 and F3 generations. Prostate disease, ovarian primordial follicle loss and polycystic ovary disease were increased in F1 generation dioxin lineage. Kidney disease in males, pubertal abnormalities in females, ovarian primordial follicle loss and polycystic ovary disease were increased in F3 generation dioxin lineage animals. Analysis of the F3 generation sperm epigenome identified 50 differentially DNA methylated regions (DMR) in gene promoters. These DMR provide potential epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Observations demonstrate dioxin exposure of a gestating female promotes epigenetic transgenerational inheritance of adult onset disease and sperm epimutations.
Mohan Manikkam, Rebecca Tracey, Carlos Guerrero-Bosagna, Michael K. Skinner , “Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) InduceTransgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations,” PLoS ONE, January 24, 2013, 8:1, DOI: 10.1371/journal.pone.0055387
Environmental compounds are known to promote epigenetic transgenerational inheritance of adult onset disease in subsequent generations (F1–F3) following ancestral exposure during fetal gonadal sex determination. The current study was designed to determine if a mixture of plastic derived endocrine disruptor compounds bisphenol-A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) at two different doses promoted epigenetic transgenerational inheritance of adult onset disease and associated DNA FULL TEXTepimutations in sperm. Gestating F0 generation females were exposed to either the “plastics” or “lower dose plastics” mixture during embryonic days 8 to 14 of gonadal sex determination and the incidence of adult onset disease was evaluated in F1 and F3 generation rats. There were significant increases in the incidence of total disease/abnormalities in F1 and F3 generation male and female animals from plastics lineages. Pubertal abnormalities, testis disease, obesity, and ovarian disease (primary ovarian insufficiency and polycystic ovaries) were increased in the F3 generation animals. Kidney and prostate disease were only observed in the direct fetally exposed F1 generation plastic lineage animals. Analysis of the plastics lineage F3 generation sperm epigenome previously identified 197 differential DNA methylation regions (DMR) in gene promoters, termed epimutations. A number of these transgenerational DMR form a unique direct connection gene network and have previously been shown to correlate with the pathologies identified. Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease. The sperm DMR provide potential epigenetic biomarkers for transgenerational disease and/or ancestral environmental exposures.
Mohan Manikkam, M. Muksitul Haque, Carlos Guerrero-Bosagna, Eric E. Nilsson, Michael K. Skinner , “Pesticide Methoxychlor Promotes theTransgenerational Inheritance of Adult-Onset Disease through the Female Germline,” PLoS ONE, 2014, 9:7, DOI: 10.371/JOURNAL.PONE.0102091.
Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA FULL TEXTregions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.
Neila Marouani, Olfa Tebourbi, Donia Cherif, Dorsaf Hallegue, Mohamed Tahar Yacoubi, Mohsen Sakly, Moncef Benkhalifa, Khemais Ben Rhouma, “Effects of oral administration of 2,4-dichlorophenoxyacetic acid (2,4-D) on reproductive parameters in male Wistar rats,” Environmental Science and Pollution Research, January 2017, Volume 24:1, DOI: 10.1007/s11356-016-7656-3.
The 2,4-dichlorophenoxyacetic acid (2,4-D) is used worldwide in agriculture as a selective herbicide. It has been shown to produce a wide range of adverse effects on the health of both animals and humans from embryotoxicity and teratogenicity to neurotoxicity. In the present study, we have examined the effect of 2,4-D on male reproductive function of rats. Male Wistar rats received daily by force-feeding 100 or 200 mg of 2,4-D/kg body weight for 30 consecutive days. Rats exposed to 100 and 200 mg of 2,4-D/kg showed a significant decrease in body weights only after 24 days of treatment and in relative weights of testis, seminal vesicles and prostate at killing day, when compared with controls. Moreover, a decrease in testosterone and an increase in FSH and LH serum levels were detected in treated rats. Besides, exposure to this herbicide induced pronounced testicular histological alterations with enlarged intracellular spaces, tissue loosening and dramatic loss of gametes in the lumen of the seminiferous tubules. In addition, a decreased motility and a number of epididymal spermatozoa with an increased sperm abnormality rate were found in treated rats in comparison with control. With the highest dose, histological observations of seminal vesicles indicated a considerable decrease of secretions in the lumen, a thinness of the muscle layer surrounding the epithelium with branched mucosal crypts and reduced luminal space. In prostate, the heights of the cells decreased while acinar lumen were enlarged and they lost the typical invaginations. Our results suggest that a subacute treatment of 2,4-D promotes reproductive system toxicity.
Margaux McBirney, Stephanie E. King, Michelle Pappalardo, Elizabeth Houser, Margaret Unkefer, Eric Nilsson, Ingrid Sadler-Riggleman, Daniel Beck, Paul Winchester, Michael K. Skinner, “Atrazine inducedtransgenerational inheritance of disease, lean and sperm epimutation pathology biomarkers,” PLOS One, 2017, 12:9, DOI: 10.1371/journal.pone.0184306
Ancestral environmental exposures to a variety of environmental toxicants and other factors have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The current study examined the potential transgenerational actions of the herbicide atrazine. Atrazine is one of the most commonly used herbicides in the agricultural industry, in particular with corn and soy crops. Outbred gestating female rats were transiently exposed to a vehicle control or atrazine. The F1 generation offspring were bred to generate the F2 generation and then the F2 generation bred to generate the F3 generation. The F1, F2 and F3 generation control and atrazine lineage rats were aged and various pathologies investigated. The male sperm were collected to investigate DNA FULL TEXTdifferences between the control and atrazine lineage sperm. The F1 generation offspring (directly exposed as a fetus) did not develop disease, but weighed less compared to controls. The F2 generation (grand-offspring) was found to have increased frequency of testis disease and mammary tumors in males and females, early onset puberty in males, and decreased body weight in females compared to controls. The transgenerational F3 generation rats were found to have increased frequency of testis disease, early onset puberty in females, behavioral alterations (motor hyperactivity) and a lean phenotype in males and females. The frequency of multiple diseases was significantly higher in the transgenerational F3 generation atrazine lineage males and females. The transgenerational transmission of disease requires germline (egg or sperm) epigenetic alterations. The sperm differential DNA methylation regions (DMRs), termed epimutations, induced by atrazine were identified in the F1, F2 and F3 generations. Gene associations with the DMRs were identified. For the transgenerational F3 generation sperm, unique sets of DMRs (epimutations) were found to be associated with the lean phenotype or testis disease. These DMRs provide potential biomarkers for transgenerational disease. The of disease appears to be in part due to environmentally induced epigenetic transgenerational inheritance, and epigenetic biomarkers may facilitate the diagnosis of the ancestral exposure and disease susceptibility. Observations indicate that although atrazine does not promote disease in the directly exposed F1 generation, it does have the capacity to promote the epigenetic transgenerational inheritance of disease.