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- New signaling pathways associated with mitochondrial dysfunction induced by obesogens in Sertoli cellsPublication . Bastos, Ana Luísa Marques de; Rato, Luís Pedro Ferreira; Sousa, Ana Catarina; Silva, Branca Maria Cardoso Monteiro daIn recent years, obesity has emerged as a significant public health concern, particularly with regard to its effects on male fertility. Of particular interest is the role of obesogens, a class of environmental chemicals implicated in the development of obesity. These compounds are increasingly recognized as major contributors to excessive weight gain, primarily due to their function as endocrine-disrupting chemicals (EDCs), which interfere with hormonal regulation and metabolic processes. Tributyltin (TBT), a welldocumented obesogen, is recognized as one of the most toxic compounds introduced into ecosystems. Owing to its lipophilic properties, TBT exhibits a strong tendency to bioaccumulate in lipid-dense tissues, including the testes. Upon accumulation in these organs, TBT can interfere with critical physiological and metabolic processes necessary for spermatogenesis and steroidogenesis. This disruption may lead to detrimental reproductive outcomes, including elevated oxidative stress (OS) within the testes and the manifestation of sperm abnormalities. Sertoli cells (SCs), which play a crucial role in providing nutritional and structural support to developing and maturing germ cells, are especially susceptible to these disruptions. SCs have been identified as primary targets of environmental toxicants, which can significantly impair their structural integrity and functional capacity. Furthermore, the hypothalamic-pituitary-testicular (HPT) axis, commonly known as the reproductive axis, exhibits marked sensitivity to metabolic disruptions induced by environmental toxicants, potentially resulting in compromised reproductive function. This study sought to elucidate the relationship between TBT exposure and male infertility by investigating the deleterious effects of this obesogen on SCs mitochondrial function and its broader implications for male reproductive health. To accomplish this objective, an animal model was employed to assess the expression of key proteins involved in the regulation of mitochondrial biogenesis and the activation of the antioxidant defense system. Two concentrations of TBT were evaluated: 0,1 nM, a sub-toxic dose known to activate the retinoid X receptor/peroxisome proliferatoractivated receptor gamma (RXR/PPAR?) heterodimer, and 10 nM, a concentration comparable to the levels detected in the serum and tissues of certain individuals. The results demonstrated that exposure to the highest concentration of TBT (10 nM) elicited the most pronounced effects on SCs. Nevertheless, significant alterations were also observed at the sub-toxic concentration of 0,1 nM, indicating that even low-level exposure to TBT can induce substantial cellular and functional changes. The antioxidant capacity of Sertoli cells (SCs) was assessed, revealing a reduction following exposure to both concentrations of TBT (10 nM and 0,1 nM). Additionally, oxidative stress-induced damage was evaluated, encompassing measurements of protein carbonylation and lipid peroxidation. Lipid peroxidation was found to decrease following exposure to the highest concentration of TBT (10 nM), whereas a slight increase was observed at the lower concentration (0,1 nM). Regarding protein oxidation, levels of carbonylation decreased in response to both concentrations of TBT. Several molecular regulators were also affected by TBT exposure, with increased expression observed for sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) at both concentrations. In contrast, levels of sirtuin 3 (SIRT3) were found to be diminished following TBT exposure. Additionally, other regulators of PGC-1a were also impacted, including a decrease in CREB-binding protein (CBP) at both concentrations. Notably, acetylated CREB-binding protein (A-CBP) and homolog 2 of the general control of amino acid synthesis in yeast (GCN2) exhibited an increase at 10 nM TBT, while levels decreased at the lower concentration of 0,1 nM. Conversely, the p300/CBP-associated factor (PCAF) demonstrated an inverse pattern, with levels increasing at 0.1 nM TBT and decreasing at 10 nM. The results indicate that exposure to TBT induces significant alterations in the expression of key regulators of mitochondrial biogenesis within reproductive organs, thereby disrupting the molecular pathways essential for mitochondrial function. This dysregulation compromises the integrity of the antioxidant defense system, which is crucial for cellular homeostasis. Expanding our understanding of mitochondrial bioenergetics is therefore essential for devising strategies to combat the increasing prevalence of male infertility, particularly in developed countries, where metabolic disorders are increasingly acknowledged as significant public health concerns.