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.

Proteomic Profiles of Thyroid Gland and Gene Expression of the Hypothalamic-Pituitary-Thyroid Axis Are Modulated by Exposure to AgNPs during Prepubertal Rat Stages.

Silver nanoparticles (AgNPs) have potent antimicrobial activity and, for this reason, are incorporated into a variety of products, raising concern about their potential risks and impacts on human health and the environment. The developmental period is highly dependent on thyroid hormones (THs), and puberty is a sensitive period, where changes in the hormonal environment may have permanent effects. We evaluated the hypothalamic-pituitary (HP)-thyroid axis after exposure to low doses of AgNPs using a validated protocol to assess pubertal development and thyroid function in immature male rats. For stimulatory events of the HP-thyroid axis, we observed an increase in the expression of Trh mRNA and serum triiodothyronine. Negative feedback reduced the hypothalamic expression of Dio2 mRNA and increased the expression of Thra1, Thra2, and Thrb2 mRNAs. In the pituitary, there was a reduced expression of Mct-8 mRNA and Dio2 mRNA. For peripheral T3-target tissues, a reduced expression of Mct-8 mRNA was observed in the heart and liver. An increased expression of Dio3 mRNA was observed in the heart and liver, and an increased expression of Thrb2 mRNA was observed in the liver. The quantitative proteomic profile of the thyroid gland indicated a reduction in cytoskeletal proteins (Cap1, Cav1, Lasp1, Marcks, and Tpm4; 1.875 µg AgNP/kg) and a reduction in the profile of chaperones (Hsp90aa1, Hsp90ab1, Hspa8, Hspa9, P4hb) and proteins that participate in the N-glycosylation process (Ddost, Rpn1 and Rpn2) (15 µg AgNP/kg). Exposure to low doses of AgNPs during the window of puberty development affects the regulation of the HP-thyroid axis with further consequences in thyroid gland physiology.

Prepubertal acrylamide exposure causes dose-response decreases in spermatic production and functionality with modulation of genes involved in the spermatogenesis in rats.

The increase in human infertility prevalence due to male reproductive disorders has been associated with extensive endocrine-disrupting chemical (EDC) exposure. Acrylamide (AA) is a compound formed spontaneously during heat processing of some foods that are mainly consumed by children and adolescents. In this study, we evaluated the prepubertal AA exposure effects on male adult reproductive physiology using a prepubertal experimental model to analyze the pubertal development, spermatogenesis hormones levels and genes expression involved in male reproductive function. This study is the first one to use the validated protocol to correlate the AA exposure with puberty development, as well as the AA-induced endocrine disrupting effects on reproductive axis. AA did not affect the age at puberty, the reproductive organ's weight and serum hormonal levels. AA reduces spermatogenesis, induces morphological and functional defects on sperm and alters transcript expression of sexual hormone receptors (Ar and Esr2), the transcript expression of Tnf, Egr2, Rhcg and Lrrc34. These findings suggest that excessive AA consumption may impair their reproductive capacity at adulthood, despite no changes in hormonal profile being observed.

Imbalanced testicular metabolism induced by thyroid disorders: New evidences from quantitative proteome.

Thyroid dysfunctions, such as hypothyroidism and hyperthyroidism, are the second most prevalent endocrinopathies and are associated to reproductive disorders in men. Several genes are differentially modulated by thyroid hormones in testes and imbalances in thyroid hormone levels are also associated to alterations on sperm functionality. Imbalances on antioxidant defense mechanism and stress oxidative have been pointed out as the main factors for the impairments on male reproductive function. To clarify this issue, we investigated the expression and activity of antioxidant enzymes in testis, followed by their proteomic profile in attempt to characterize the mechanisms involved in the alterations induced by hypo- or hyperthyroidism in adult male rats. Hypothyroidism reduced the Gsr transcript expression and the activity of CAT and GSR enzymes, while the hyperthyroidism reduced the Gpx4 var2 transcript expression. Among 1082 identified proteins, 123 and 37 proteins were downregulated by hypothyroidism compared to euthyroid and hyperthyroid condition, respectively, being 36 proteins commonly reduced in both comparisons and one exclusively in hypo-hyperthyroidism comparison. A network containing 29 nodes and 68 edges was obtained in protein-protein interaction analysis and the functional enrichment analysis of differentially expressed proteins revealed significant alterations for several functions in hypo-euthyroid and hypo-hyperthyroid comparisons, such as ATP metabolic process, coenzyme binding, sperm part, peroxiredoxin activity, mitochondrial protein complex, intramolecular oxidoreductase activity, binding of sperm to zona pellucida, glutathione transferase activity, response to testosterone. Thus, there is a correlation between thyroid disorders and impaired antioxidant defense mechanism, resulting in reproductive dysfunctions, as infertility, mainly observed in hypothyroidism.

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.