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Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of GBH added to the CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: control, CAF, GBH, and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. With respect to the control group, no changes in the serum levels of 17ß-estradiol and progesterone were found. However, progesterone levels were higher in the CAF+GBH group than in the CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with the CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, with respect to control rats. These results indicate that the addition of GBH exacerbates the CAF effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies.

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Mesolimbic dopaminergic circuit is essential for food reward and motivational behaviors and can contribute to weight gain and obesity. Litter reduction is a classical model for studying the effects of neonatal overfeeding and overweight. Litters of Wistar rats were reduced to 4 pups/dam for small litter (SL) and 10 pups/dam for normal litter at postnatal day (PND) 4. Immediately after performing the feeding behavior tests, the animals were sacrificed in PND21 and PND90. The ventral tegmental area (VTA), Nucleus Accumbens Core (NAcC) and Shell (NAcSh) were isolated from frozen brain sections using the Palkovits micropunch technique. RNA and DNA were extracted from these areas, gene expression was measured by RT-qPCR and DNA methylation levels were measured by MSRM-qPCR technique. SL-PND21 animals presented increased expression levels of Tyrosine Hydroxylase and Dopamine Receptor D2 in VTA, decreased expression levels of dopamine active transporter (DAT) in VTA, and higher expression levels of DAT in NAcC. On the other hand, SL-PND90 animals showed decreased expression levels of Dopamine Receptor D1 and higher expression of DAT in NAcSh. These animals also evidenced impaired sensory-specific satiety. In addition, altered promoter methylation was observed at weaning, and remained in adulthood. This work demonstrates that neonatal overfeeding induces disruptions in the mesolimbic dopaminergic circuitry and causes alterations in feeding behavior from weaning to adulthood, suggesting that the neonatal period is critical for the normal development of dopaminergic circuit that impact on feeding behavior.

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Neurosteroids are steroids synthesized de novo from cholesterol in brain regions, and regulate processes associated with the development and functioning of the nervous system. Enzymes and proteins involved in the synthesis of these steroids have been detected in several brain regions, including hippocampus, hypothalamus, and cerebral cortex. Hippocampus has long been associated with learning and memory functions, while the loss of its functionality has been linked to neurodegenerative pathologies. In this sense, neurosteroids are critical for the maintenance of hippocampal functions and neuroprotective effects. Moreover, several factors have been shown to deregulate expression of steroidogenic enzymes in the rodent brain, including aging, enrichment experiences, diet habits, drug/alcohol consumption, hormone fluctuations, neurodegenerative processes and other diseases. These transcriptional deregulations are mediated mainly by transcription factors and epigenetic mechanisms. An epigenetic modification of chromatin involves changes in bases and associated proteins in the absence of changes in the DNA sequence. One of the most well-studied mechanisms related to gene silencing is DNA methylation, which involves a reversible addition of methyl groups in a cytosine base. Importantly, these epigenetic marks could be maintained over time and could be transmitted transgenerationally. The aim of this chapter is to present the most relevant steroidogenic enzymes described in rodent hippocampus; to discuss about their transcriptional regulation under different conditions; to show the main gene control regions and to propose DNA methylation as an epigenetic mechanism through which the expression of these enzymes could be controlled.

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Glyphosate base herbicides (GBHs) are the most widely applied pesticides in the world and are mainly used in association with GBH-tolerant crop varieties. Indiscriminate and negligent use of GBHs has promoted the emergence of glyphosate resistant weeds, and consequently the rise in the use of these herbicides. Glyphosate, the active ingredient of all GBHs, is combined with other chemicals known as co-formulants that enhance the herbicide action. Nowadays, the safety of glyphosate and its formulations remain to be a controversial issue, as evidence is not conclusive whether the adverse effects are caused by GBH or glyphosate, and little is known about the contribution of co-formulants to the toxicity of herbicides. Currently, alarmingly increased levels of glyphosate have been detected in different environmental matrixes and in foodstuff, becoming an issue of social concern. Some in vitro and in vivo studies have shown that glyphosate and its formulations exhibit estrogen-like properties, and growing evidence has indicated they may disrupt normal endocrine function, with adverse consequences for reproductive health. Moreover, multigenerational effects have been reported and epigenetic mechanisms have been proved to be involved in the alterations induced by the herbicide. In this review, we provide an overview of: i) the routes and levels of human exposure to GBHs, ii) the potential estrogenic effects of glyphosate and GBHs in cell culture and animal models, iii) their long-term effects on female fertility and mechanisms of action, and iv) the consequences on health of successive generations.

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Glyphosate is a phosphonomethyl amino acid derivative present in a number of non-selective and systemic herbicides. During the last years the use of glyphosate-based herbicide (GBH) has been increasing exponentially around the world, including Argentina. This fact added to the detection of glyphosate, and its main metabolite, amino methylphosphonic acid (AMPA), in environmental matrices such as soil, sediments, and food, has generated great concern about its risks for humans, animals, and environment. During the last years, there were controversy and intense debate regarding the toxicological effects of these compounds associated with the endocrine system, cancer, reproduction, and development. The mechanisms of action of GBH and their metabolites are still under investigation, although recent findings have shown that they could comprise epigenetic modifications. These are reversible mechanisms linked to tissue-specific silencing of gene expression, genomic imprinting, and tumor growth. Particularly, glyphosate, GBH, and AMPA have been reported to produce changes in global DNA methylation, methylation of specific genes, histone modification, and differential expression of non-coding RNAs in human cells and rodents. Importantly, the epigenome could be heritable and could lead to disease long after the exposure has ended. This mini-review summarizes the epigenetic changes produced by glyphosate, GBHs, and AMPA in humans and rodents and proposes it as a potential mechanism of action through which these chemical compounds could alter body functions.

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