Silver nanoparticles (AgNPs) are widely used in industrial and medical applications and humans may be exposed through different routes, increasing the risk of toxicity. We investigated the transcript expression of genes involved in the regulation of the hypothalamic-pituitary-testicular (HPT) axis and the parameters associated with sperm functionality after prepubertal exposure. AgNPs modulated the transcript expression of genes involved in the control of the HPT axis and spermatogenesis in the groups treated with lower doses, while the functional parameters related to sperm and puberty were affected in the groups administered higher doses. These results suggest that the HPT axis is disrupted by AgNPs during the prepubertal and pubertal periods, which are highly susceptible windows for the endocrine-disrupting chemical activity.

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.

Bisphenol A (BPA) is a synthetic endocrine-disrupting chemical of high prevalence in the environment, which may affect the function of the hypothalamic-pituitary-testis (HPT) axis in adult rats. The aim of the present study was to evaluate whether exposure to BPA during hypothalamic sexual differentiation at doses below the reproductive no observable adverse effect level of the World Health Organization causes changes in the regulation of the HPT axis. For this, 0.5 or 5mgkg BPA was injected subcutaneously to the mothers from gestational day 18 to postnatal day (PND) 5. In adulthood (PND90), the mRNA expression of genes related to HPT axis was evaluated in hypothalamus, pituitary and testis. Hypothalamic expression of gonadotrophin-releasing hormone (Gnrh) and estrogen receptor 2 (Esr2) mRNA was increased in both BPA-treated groups compared to control group. In the pituitary, follicle stimulating hormone beta subunit (Fshb) and androgen receptor (Ar) mRNA expression was increased compared to control group in rats treated with 0.5mgkg of BPA, whereas estrogen receptor 1 (Esr1) mRNA expression was only increased in the group treated with 5mgkgof BPA, compared to control group. In the testis, there was increased expression of FSH receptor (Fshr) and inhibin beta B subunit (Inhbb) transcripts only in rats treated with 0.5mgkg of BPA. Serum testosterone and LH concentrations were increased in the group treated with 5mgkgof BPA. The results of the present study demonstrate for the first time that perinatal exposure to low doses of BPA during the critical period of hypothalamic sexual differentiation modifies the activity of the HPT axis in the offspring, with consequences for later life in adult rats.

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.

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