Multi-omics Investigations in Endocrine Systems and Their Clinical Implications.

Innovative techniques such as the "omics" can be a powerful tool for the understanding of intracellular pathways involved in homeostasis maintenance and identification of new potential therapeutic targets against endocrine-metabolic disorders. Over the last decades, proteomics has been extensively applied in the study of a wide variety of human diseases, including those involving the endocrine system. Among the most endocrine-related disorders investigated by proteomics in humans are diabetes mellitus and thyroid, pituitary, and reproductive system disorders. In diabetes, proteins implicated in insulin signaling, glucose metabolism, and ß-cell activity have been investigated. In thyroid diseases, protein expression alterations were described in thyroid malignancies and autoimmune thyroid illnesses. Additionally, proteomics has been used to investigate the variations in protein expression in adrenal cancers and conditions, including Cushing's syndrome and Addison's disease. Pituitary tumors and disorders including acromegaly and hypopituitarism have been studied using proteomics to examine changes in protein expression. Reproductive problems such as polycystic ovarian syndrome and endometriosis are two examples of conditions where alterations in protein expression have been studied using proteomics. Proteomics has, in general, shed light on the molecular underpinnings of many endocrine-related illnesses and revealed promising biomarkers for both their detection and treatment. The capacity of proteomics to thoroughly and objectively examine complex protein mixtures is one of its main benefits. Mass spectrometry (MS) is a widely used method that identifies and measures proteins based on their mass-to-charge ratio and their fragmentation pattern. MS can perform the separation of proteins according to their physicochemical characteristics, such as hydrophobicity, charge, and size, in combination with liquid chromatography. Other proteomics techniques include protein arrays, which enable the simultaneous identification of several proteins in a single assay, and two-dimensional gel electrophoresis (2D-DIGE), which divides proteins depending on their isoelectric point and molecular weight. This chapter aims to summarize the most relevant proteomics data from targeted tissues, as well as the daily rhythmic variation of relevant biomarkers in both physiological and pathophysiological conditions within the involved endocrine system, especially because the actual modern lifestyle constantly imposes a chronic unentrained condition, which virtually affects all the circadian clock systems within human's body, being also correlated with innumerous endocrine-metabolic diseases.

Prepubertal to adulthood exposure to low doses of glyphosate-based herbicide increases the expression of the Havcr1 (Kim1) biomarker and causes mild kidney alterations.

Glyphosate is a nonselective and postemergent herbicide used to combat weeds in several crops, which raises concerns about risks to human health since residues are detected in urine, human milk, surface water and several types of food. Feces and urine are the major routes of elimination of glyphosate, making the kidney a sensitive target for the development of toxicity. In fact, farmers are at high risk of developing chronic kidney disease. In this sense, this study aims to investigate kidney function by measuring the serum levels of urea and creatinine, examining the histological morphology, and analyzing the mRNA expression of genes related to tubular transport of ions, urea and urates and the biomarker of kidney disease Kim1, and the levels of lead in the kidney in male Wistar rats orally exposed to low levels of glyphosate-based herbicide (GBH: 0, 0.5 or 5 mg/kg) from weaning to adult life by gavage. GBH0.5 showed reduced serum urea concentration, presence of tubulointerstitial swelling and mononuclear cell infiltration into the interstitium, increased gene expression of Kim1 and reduced gene expression of Slc14a1. GBH5 showed reduced serum urea and increased serum creatinine concentrations, tubulointerstitial swelling, interstitial fibrosis, and reduced expression of Trpm6 and Trpv5. Exposure to GBH did not affect the levels of Pb in the kidneys of animals. In conclusion, glyphosate at low doses may cause mild kidney damage. It is necessary to evaluate whether the long-term effects of this constant injury may contribute to the development of chronic kidney disease of uncertain etiology.

Effects of Silver Nanoparticle Exposure to the Testicular Antioxidant System during the Prepubertal Rat Stage.

Humans and environments are constantly exposed to a wide range of commercial products containing silver nanoparticles (AgNPs) in their composition. The hypothalamic-pituitary-testicular (HP-testicular) axis is sensitive to low doses of AgNPs with repercussions in sperm functionality. The oxidative stress may be related to the pathogenesis of sperm alterations because Ag+ ions are released from AgNPs in the corporal fluids. This study aimed to investigate the effects of AgNP exposure in the antioxidant defense system. For this, the transcript expression and the activity of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione reductase (GSR) enzymes were evaluated in the testis of rats exposed during the prepubertal period to increasing doses of AgNPs (1.875, 3.75, 7.5, or 15 µg of AgNPs/kg). The higher dose of AgNPs (15 µg/kg) investigated promoted increases in the activity of CAT, GPX, and GSR enzymes and in the expression of Gpx4 var1 transcript. The exposure to 7.5 µg/kg of AgNP increased the Gpx4 var1 mRNA expression. In the group that received 3.75 µg of AgNP/kg, the expression of Sod1, Gpx4 var2, and Gsr transcripts was decreased while the Gpx4 var1 mRNA expression was augmented. The lower dose of AgNPs tested (1.875 µg/kg) increased the expression of Cat and Gpx4 var1 transcripts. Thus, AgNP alters the expression and activity of the antioxidant enzymes in a nonmonotonic dose-response curve and directly or indirectly modulates the events related to spermatogenesis process.

Maternal bisphenol A exposure disrupts spermatogenesis in adult rat offspring.

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that is widely used in the manufacturing of plastics and inner linings of food cans. Previously, it was reported that BPA disturbed the sexual dimorphic nucleus of the hypothalamus and delaying the onset of puberty attributed to an estrogenic action. In addition, BPA during the perinatal period increased LH serum concentrations in male offspring of dams at doses below the reproductive NOAEL (No Observable Adverse Effect Level) based upon World Health Organization guidelines. Based upon these findings, the objective of this study was to (1) determine the effects of perinatal treatment with low doses of BPA on regulation of spermatogenesis in adult offspring and (2) elucidate molecular mechanisms involved in the pathogenesis of gonadal dysfunction. The expression of genes related to spermatogenesis was disrupted with adverse consequences on sperm production, reserves, and function. Both BPA treated groups exhibited reduction in sperm production and epithelial height of seminiferous tubules, accompanied by diminished integrity of the acrosome and plasma membrane, decreased mitochondrial activity and increased incidence of morphological abnormalities. The sperm transit time was also slower. However, only in the group receiving the higher BPA dose was transcript expression of genes affected (reduced Ar and increased Esr1). It is of interest that serum testosterone levels were elevated in the same group where Ar was decreased. Data suggest that exposure to low BPA doses during hypothalamic sexual differentiation period produces permanent deleterious effects on spermatogenesis in adulthood.

Evaluation of neuroglobin and cytoglobin expression in adult rats exposed to silver nanoparticles during prepubescence.

Silver nanoparticles (AgNPs) are clusters of silver atoms with diameters that range from 1 to 100 nm. Due to the various shapes and large surface areas, AgNPs have been employed in the food and textile industries and medical fields. Therefore, because of the widespread use of these compounds, the aim of this study was to evaluate the effect of AgNP exposure on the gene and protein expression levels of Neuroglobin (Ngb) and Cytoglobin (Cygb), in the rat cortex, hippocampus and cerebellum. Post-natal day (PND) 21 male Wistar rats were randomly divided into three groups. One group received 15 µg/kg body weight of AgNP by gavage another group received 30 µg/kg and the control group that received saline, from PND23 to PND58. On PND102 the animals were euthanized and the cortex, hippocampus and cerebellum were isolated and evaluated for gene and protein expression levels of Nbg and Cygb. The results demonstrated that the 30 µg/kg AgNP group displayed increased gene and protein expression of Cygb in the cortex. In the Hippocampus, AgNP exposure did not modulate gene or protein expression levels of Ngb and Cygb. In cerebellum the Ngb gene and protein expression was increased with both doses of AgNP. AgNP exposure during prepubescence can modulate the gene and protein expression levels of Ngb and Cygb in adulthood. Furthermore, the observed modulation was specific to the cerebellum, and cortex, and was dose dependent.

Anatomical specificity of the brain in the modulation of Neuroglobin and Cytoglobin genes after chronic bisphenol a exposure.

The aim of this study was to investigate the influence of Bisphenol A (BPA) exposure on Neuroglobin (Ngb) and Cytoglobin (Cygb) as well as oxidative stress gene expression in the cerebellum, hippocampus, hypothalamus and cortex. Male Wistar rats were randomly divided into 3 groups: Control and two groups receiving 2 different daily BPA dosages, 5 or 25 mg/kg from postnatal day 50 (PND50) through PND90 and they were euthanized at PND105. In the cortex, we found an increase in Ngb gene expression and also in superoxide dismutase 1 and Catalase (Cat). In the cerebellum, we found an increase in Ngb and Cat, in the hypothalamus, there was a decrease in Cygb and an increase in glutathione peroxidase and Cat and in hypoxia-inducible factor 1 alpha (Hif1α) at the low dosage and a decrease in Hif1α at the high BPA dosage. Finally, in the hippocampus, we observed a decrease in Ngb and Cygb and an increase in Hif1α. In summary, BPA promotes the modulation of both Ngb and Cygb, but such changes occur by different mechanisms depending on the exposure dose and anatomical area.

A System Biology Approach Reveals New Targets for Human Thyroid Gland Toxicity in Embryos and Adult Individuals.

Compounds of natural or synthetic origin present in personal care products, food additives, and packaging may interfere with hormonal regulation and are called endocrine-disrupting chemicals (EDCs). The thyroid gland is an important target of these compounds. The objective of this study was to analyze public data on the human thyroid transcriptome and investigate potential new targets of EDCs in the embryonic and adult thyroid glands. We compared the public transcriptome data of adult and embryonic human thyroid glands and selected 100 up- or downregulated genes that were subsequently subjected to functional enrichment analysis. In the embryonic thyroid, the most highly expressed gene was PRMT6, which methylates arginine-4 of histone H2A (86.21%), and the downregulated clusters included plasma lipoprotein particles (39.24%) and endopeptidase inhibitory activity (24.05%). For the adult thyroid gland, the most highly expressed genes were related to the following categories: metallothionein-binding metals (56.67%), steroid hormone biosynthetic process (16.67%), and cellular response to vascular endothelial growth factor stimulus (6.67%). Several compounds ranging from antihypertensive drugs to enzyme inhibitors were identified as potentially harmful to thyroid gland development and adult function.

Effects of prepubertal exposure to silver nanoparticles on reproductive parameters in adult male Wistar rats.

The incidence of male reproductive pathologies, such as hypospadias, cryptorchidism, testicular cancer, and low sperm production in adulthood, is increasing and may be related to exposure to environmental contaminants. The silver nanoparticles (AgNP) are a new class of chemical compounds commonly used in both medical and nonmedical settings, and they affect development of spermatogonial stem cells in vitro. The aim of this study was to examine the adverse productive toxic effects of AgNPs in male Wistar rats exposed during the prepubertal period and sacrificed at postnatal day (PND) 53 and PND90. Growth was assessed by daily weighing. The progress of puberty in the rats was measured by preputial separation, while spermatogenesis was assayed by (1) measuring the sperm count in testes and epididymis and (2) examining the morphology and morphometry of seminiferous epithelium using stereological analysis. In addition, testosterone and estradiol levels were assayed by radioimmunoassay. The weight of the animals at PND90 did not change markedly, but growth was less in the group treated with AgNP at 50 µg/kg from PND34 to PND53. AgNP exposure produced a delay in puberty in both treated groups. Decreased sperm reserves in the epididymis and diminished sperm transit time were observed at PND53, while a reduction in sperm production occurred at PND90. The morphology of the seminiferous epithelium was markedly altered. Data demonstrated that prepubertal exposure to AgNP altered reproductive development in prepubertal male Wistar rats, as evidenced by impairment in spermatogenesis and a lower sperm count in adulthood.

Quantitative proteomic profile analysis of thyroid dysfunction effects on seminal vesicles and repercussions on male fertility.

Hypothyroidism and thyrotoxicosis are associated with male reproductive disorders, but little is known about the influence of the thyroid hormone milieu on seminal vesicle (SV) function and metabolism. In this sense, we investigated the effects of hypothyroidism and thyrotoxicosis induced in adulthood Wistar male rats on SV function and identified new thyroid hormone targets on male reproduction regulation using novel proteomic approaches. Hypothyroidism reduces SV size and seminal fluid volume, which are directly associated with low testosterone and estradiol levels, while thyrotoxicosis increases Esr2 and Dio1 expression in the SV. We found 116 differentially expressed proteins. Hypothyroidism reduces the expression of molecular protein markers related to sperm viability, capacitation and fertilization, protection against oxidative stress and energetic metabolism in SV, while it increases the expression of proteins related to tissue damage. In conclusion, thyroid dysfunction in the adult phase impairs several morphological, molecular and functional characteristics of SV.

The effects of glyphosate-based herbicide on the hypothalamic-pituitary thyroid axis are tissue-specific and dependent on age exposure.

The significant increase in glyphosate-based herbicide (GBH) use raises concerns about residues in the environment and food, potentially jeopardizing human health. The involvement of GBHs in the increased incidence of thyroid disorders is speculated, since glyphosate has been linked to an increased risk of thyroid disease in farmers. In this sense, this study aims to investigate the potential effects of low levels of GBH exposure (0, 0.5 or 5 mg/kg) from weaning (postnatal day PND23) to adult life (PND60 and PND90) in male Wistar rats on hypothalamic-pituitary-thyroid (HPT) axis function. The serum levels of T4 were increased. The hypothalamus showed reduced expression of Dio2, Thra1, and Thra2. The pituitary showed reduced expression of Mct8 and Dio2 and increased expression of Thra1. The thyroid showed increased expression of Tshr and Thra1. The heart showed increased expression of Mct8 and Myh6. The liver showed reduced expression of Mct8 and Thra2 and increased expression of Thra1. In thyroid morphometry, a decrease in both follicular diameter and area and decreased follicular and colloid diameters and areas were observed. These results suggested that GBH may affect several steps of HPT axis regulation at the transcriptional level in an age-dependent manner and alter the morphometric parameters of the thyroid gland and TH synthesis, with potential repercussions in the TH-target organs.

Prepubertal oral exposure to relevant doses of acrylamide impairs the testicular antioxidant system in adulthood, increasing protein carbonylation and lipid peroxidation.

The increased prevalence of human infertility due to male reproductive disorders has been linked to extensive exposure to chemical endocrine disruptors. Acrylamide (AA) is a compound formed spontaneously during the thermal processing of some foods that are mainly consumed by children and adolescents. We previously found that prepubertal exposure to AA causes reduced sperm production and functionality. Oxidative stress is recognized as the main cause of reduced sperm quality and quantity. In this sense, our objective was to evaluate the expression and activity of genes related to enzymatic antioxidant defense, nonprotein thiols, lipid peroxidation (LPO), protein carbonylation (PC) and DNA damage in the testes of rats exposed to acrylamide (2.5 or 5 mg/kg) from weaning to adult life by gavage. For the AA2.5 and AA5 groups, there were no alterations in the transcript expression of genes related to enzymatic antioxidant defense. The enzymatic activities and metabolic parameters were also not affected in the AA2.5 group. For the AA5 group, the enzymatic activities of G6PDH and GPX were reduced, SOD was increased, and protein carbonylation (PC) was increased. Data were also evaluated by Integrate Biomarker Response (IBRv2), a method to analyze and summarize the effects on biomarkers between doses. The IBRv2 index was calculated as 8.9 and 18.71 for AA2.5 and AA5, respectively. The following biomarkers were affected by AA2.5: decreased enzymatic activities of G6PDH, SOD, and GPX, increased GST and GSH, increased LPO and PC, and decreased DNA damage. For AA5, decreased enzymatic activities of G6PDH, GST, CAT and GPX, increased SOD and GSH, increased PC, and decreased LPO and DNA damage were observed. In conclusion, AA exposure during the prepubertal period causes imbalances in the testicular enzymatic antioxidant defense, contributing to the altered spermatic scenario in the testes of these rats.

Peripubertal soy isoflavone consumption leads to subclinical hypothyroidism in male Wistar rats.

Exposure to endocrine-disrupting chemicals during critical windows of development may lead to functional abnormalities in adulthood. Isoflavones are a flavonoid group of phytoestrogens that are recognized by their estrogenic activity and are highly abundant in soybean. Since the thyroid gland presents estrogen receptors and infants, toddlers and teenagers may consume isoflavones from soy-based infant formula and beverages as alternatives to animal milk, we propose to investigate the potential effects of relevant concentrations of soy isoflavones in the regulation of the hypothalamic-pituitary (HP) thyroid axis using peripubertal male rats as an experimental model. Thirty-two 23-day-old male rats were exposed to 0.5, 5, or 50 mg of soy isoflavones/kg from weaning to 60 days of age, when they were euthanized, and the tissues were collected to evaluate the mRNA expression of genes involved in the regulation of the HP thyroid axis and dosages of thyroid hormones (THs). Serum TSH concentrations were increased, while alterations were not observed in serum concentrations of triiodothyronine and thyroxine. Regarding mRNA gene expression, Mct-8 was increased in the hypothalamus, Mct-8, Thra1, and Thrb2 were decreased in the pituitary, and Nis and Pds were reduced in the thyroid. In the heart, Mct8 and Thrb2 were increased, and Thra1 was decreased. In the liver, Mct8, Thra1, and Thrb2 were decreased. These results suggest that the consumption of relevant doses of soy isoflavones during the peripubertal period in males may induce subclinical hypothyroidism, with alterations in the regulation of the HP thyroid axis, modulation of TH synthesis, and peripheral alterations in TH target organs.

Reproductive toxicity following in utero and lactational exposure to a human-relevant phthalate mixture in rats.

This rodent (Wistar rats) study examined reproductive effects of in utero/lactational exposure to a mixture of 6 antiandrogenic phthalates (PMix): diisobutyl phthalate, di-n-butyl phthalate, diisopentyl phthalate, butylbenzyl phthalate, di-2-ethylhexyl phthalate, and diisononyl phthalate. The PMix was defined based on exposure data from pregnant women in Brazil. Experimental groups were established by extrapolating the estimated human dose to rats (0.1 mg/kg/day), followed by up to 3 additional doses corresponding to 5, 1000, and 5000 times the starting rat dose: 0 (control), 0.1, 0.5, 100, and 500 mg/kg/day. The fetal experiment assessed gestational exposure effects on fetal gonads, whereas the postnatal experiment evaluated reproductive parameters in males and females after in utero and lactational exposure. Prenatal exposure decreased fetal testicular testosterone production at 0.5 and 500 mg/kg/day. PMix 500 also reduced mRNA expression of steroidogenesis-related genes, upregulated transcript expression of the retinoic acid-degrading enzyme Cyp26b1, and increased multinucleated gonocytes incidence in fetal testes. Postnatal assessment revealed antiandrogenic effects at the highest dose, including reduced anogenital distance, nipple retention, and decreased weight of reproductive organs. Early puberty onset (preputial separation) was observed at the lowest dose in males. In contrast, females did not show significant changes in fetal and adult endpoints. Overall, the PMix recapitulated early and late male rat phthalate syndrome phenotypes at the highest dose, but also induced some subtle changes at lower doses, which warrant confirmation and mechanistic assessments. Our data support the use of epidemiologically defined mixtures for exposure risk assessments over traditional toxicological approaches.

Glyphosate impairs male offspring reproductive development by disrupting gonadotropin expression.

Sexual differentiation in the brain takes place from late gestation to the early postnatal days. This is dependent on the conversion of circulating testosterone into estradiol by the enzyme aromatase. The glyphosate was shown to alter aromatase activity and decrease serum testosterone concentrations. Thus, the aim of this study was to investigate the effect of gestational maternal glyphosate exposure (50 mg/kg, NOAEL for reproductive toxicity) on the reproductive development of male offspring. Sixty-day-old male rat offspring were evaluated for sexual behavior and partner preference; serum testosterone concentrations, estradiol, FSH and LH; the mRNA and protein content of LH and FSH; sperm production and the morphology of the seminiferous epithelium; and the weight of the testes, epididymis and seminal vesicles. The growth, the weight and age at puberty of the animals were also recorded to evaluate the effect of the treatment. The most important findings were increases in sexual partner preference scores and the latency time to the first mount; testosterone and estradiol serum concentrations; the mRNA expression and protein content in the pituitary gland and the serum concentration of LH; sperm production and reserves; and the height of the germinal epithelium of seminiferous tubules. We also observed an early onset of puberty but no effect on the body growth in these animals. These results suggest that maternal exposure to glyphosate disturbed the masculinization process and promoted behavioral changes and histological and endocrine problems in reproductive parameters. These changes associated with the hypersecretion of androgens increased gonadal activity and sperm production.

Consumption of soy isoflavones during the prepubertal phase delays puberty and causes hypergonadotropic hypogonadism with disruption of hypothalamic-pituitary gonadotropins regulation in male rats.

Isoflavones are phytoestrogens with recognized estrogenic activity but may also affect testosterone, corticosterone and thyroid hormone levels in experimental models. However, the molecular mechanisms involved in these alterations are still unclear. Isoflavones are present in soy-based infant formula, in breast milk after the consumption of soy by the mother and are widely used for the preparation of beverages consumed by toddlers and teenagers. In this sense, we proposed to investigate the effects of soy isoflavone exposure during the prepubertal period, a recognized window of sensitivity for endocrine disruption, over the hypothalamic-pituitary-testicular (HPT) axis. For this, 42 3-week-old male Wistar rats were exposed to 0.5, 5 or 50 mg of soy isoflavones/kg from postnatal day (PND) 23 to PND60. We evaluated body growth, age at puberty, serum concentrations of LH, FSH, testosterone and estradiol, and the expression of the transcripts (mRNA) of genes encoding key genes controlling the hypothalamic-pituitary-testicular (HPT) axis. In the hypothalamus, we observed an increase in Esr1 mRNA expression (0.5 and 5 mg). In the pituitary, we observed an increase in Gnrhr mRNA expression (50 mg), a reduction in Lhb mRNA expression (0.5 mg), and a reduction in Ar mRNA expression. In the testis, we observed an increase in Lhcgr mRNA expression (50 mg) and a reduction in Star mRNA expression (0.5 and 5 mg). The serum levels of LH (5 and 50 mg) and FSH (0.5 mg) were increased, while testosterone and estradiol were reduced. Puberty was delayed in all groups. Taken together, these results suggest that prepubertal consumption of relevant levels of soy isoflavones disrupts the HPT axis, causing hypergonadotropic hypogonadism and altered expression levels of key genes regulating the axis.

The Analgesic Dipyrone Affects Pregnancy Outcomes and Endocrine-Sensitive Endpoints in Female and Male Offspring Rats.

Dipyrone is an analgesic and antipyretic drug commonly used in many countries. Although generally not recommended during pregnancy, it is known that many women use dipyrone during the gestational period. In this study, we investigated the endocrine and reproductive effects of dipyrone in female and male offspring rats exposed in utero from gestational days 10-21. Pregnant rats were treated with dipyrone at 25, 75, and 225 mg/kg/day via oral gavage. Developmental landmarks-anogenital index (AGI), number of nipples, vaginal opening, first estrus, and preputial separation-were evaluated in the offspring. Reproductive parameters, including estrous cycle regularity, daily sperm production, weight and histopathology of reproductive organs, steroid hormone levels, and gene expression of selected markers of reproductive function were assessed at adulthood. At the highest dose, dipyrone induced a significant increase in postimplantation losses/fetal death and delayed parturition in dams. Offspring exposed in utero to the highest dose also exhibited significant changes in some early life markers of endocrine disruption, in particular increased AGI in females, indicating a proandrogenic effect, and increased rate of retained nipples in males, indicating an antiandrogenic response. No changes were observed in markers of puberty onset or reproductive parameters at adulthood. These results suggest that exposure to therapeutically relevant doses of dipyrone may induce mild endocrine disruptive effects that can be detected in late pregnancy and early life. Such effects may be relevant considering dipyrone use by pregnant women and the possibility of coexposures with other endocrine disruptors.

Controversies on Endocrine and Reproductive Effects of Glyphosate and Glyphosate-Based Herbicides: A Mini-Review.

Glyphosate-based herbicides (GBHs) are among the most used pesticides worldwide, presenting high potential for human exposure. Recently, a debate was raised on glyphosate risks to human health due to conflicting views over its potential carcinogenic and endocrine disruptive properties. Results from regulatory guideline studies, reports from Regulatory Agencies, and some literature studies point to a lack of endocrine disrupting properties of the active ingredient glyphosate. On the other hand, many in vivo and in vitro studies, using different experimental model systems, have demonstrated that GBHs can disrupt certain hormonal signaling pathways with impacts on the hypothalamic-pituitary-gonadal axis and other organ systems. Importantly, several studies showed that technical-grade glyphosate is less toxic than formulated GBHs, indicating that the mixture of the active ingredient and formulants can have cumulative effects on endocrine and reproductive endpoints, which requires special attention from Regulatory Agencies. In this mini-review, we discuss the controversies related to endocrine-disrupting properties of technical-grade glyphosate and GBHs emphasizing the reproductive system and its implications for human health.

Could Glyphosate and Glyphosate-Based Herbicides Be Associated With Increased Thyroid Diseases Worldwide?

The increased incidence of thyroid diseases raises a series of questions about what the main predisposing factors are nowadays. If dietary restriction of iodine was once a major global health concern, today, the processes of industrialization of food and high exposure to a wide variety of environmental chemicals may be affecting, directly or indirectly, thyroid function. The homeostasis of hypothalamus-pituitary-thyroid (HPT) axis is finely regulated through the negative feedback mechanism exerted by thyroid hormones. Allostatic mechanisms are triggered to adjust the physiology of HPT axis in chronic conditions. Glyphosate and glyphosate-based herbicides are pesticides with controversial endocrine disrupting activities and only few studies have approached their effects on HPT axis and thyroid function. However, glyphosate has an electrophilic and nucleophilic zwitterion chemical structure that may affect the mechanisms involved in iodide oxidation and organification, as well as the oxidative phosphorylation in the ATP synthesis. Thus, in this review, we aimed to: (1) discuss the critical points in the regulation of HPT axis and thyroid hormones levels balance, which may be susceptible to the toxic action of glyphosate and glyphosate-based herbicides, correlating the molecular mechanisms involved in glyphosate toxicity described in the literature that may, directly or indirectly, be associated to the higher incidence of thyroid diseases; and (2) present the literature regarding glyphosate toxicity in HPT axis.

The endocrine disrupting effects of sodium arsenite in the rat testis is not mediated through macrophage activation.

Arsenic (As) is an endocrine disrupting chemical that can disturb the male reproductive system. In a previous study, it was suggested that testicular macrophages could display a role in endocrine disruption induced by As exposure. This work aimed to evaluate the effects of chronic As exposure in the testis function of Wistar rats and examine the participation of macrophage activation and inflammatory response in these processes. We examined gene expression of steroidogenic machinery and immunological markers by RT-QPCR, plasma testosterone concentrations, sperm count and morphology, and histomorphometrical parameters after 60-days exposure to 1 or 5 mg.kg-1.day-1 of sodium arsenite, combined or not with 50 µg.kg-1 of LPS administered one day before euthanasia. We have demonstrated that As exposure reduced the weight of androgen-dependent organs and induced changes in spermatogenesis, in particular at the highest dose. LPS and As co-exposure promoted a decrease in testosterone synthesis, but did not increase the overexpression of markers of macrophage activation seen in LPS-only rats. Our results suggest that As does not alter the testicular macrophage function, but under immunological challenges LPS and As can display a complex interaction, which could lead to endocrine disruption.