The increasing rate of industrialization has been implicated in the global rise in male infertility  which is majorly due to the release of endocrine disruptors into the environment. Bisphenol F is an endocrine disruptor, and little information is available about its effect on male reproduction. Although  have shown the impact of BPF on some male reproductive hormones and oxidative stress markers, there is no available information on its effect on steroidogenic enzymes and xanthine oxidase/uric acid signalling. Also, there is no available information about the after-withdrawal impact of BPF on biochemical indices and testicular histoarchitecture in male rats.
The testicular histoarchitecture of the control and control-recovery animals appeared normal. The seminiferous tubules were normal in shape with germ cells at different degrees of maturation. The seminiferous tubules' lumen showed normal cells of the sperm, and the Sertoli cells appeared normal. The interstitial space was normal with normal Leydig cell mass. BPF treatments (low, medium, and high dose) led to the distortion of testicular histoarchitecture. Some degenerated germ cell lines with scanty spermatozoa in some seminiferous tubules' lumen. Furthermore, the testicular histoarchitecture of animals in the low and medium recovery groups was distorted, evidenced by some degenerated germ cell lines, widened seminiferous tubular lumen with scanty sperm cells, and widened interstitial space with mild congestion. In addition, a gross distorted testicular histoarchitecture was observed in animals in the BPF-HR group accompanied by altered spermatogenesis, coagulative necrosis of the germ cells, scanty Sertoli cells, widened seminiferous tubular lumen with scanty or no sperm cells. There was also widened interstitial space with mild congestion and reduced Leydig cell mass. The observed distortion in the testicular histoarchitecture agreed with previously reported findings on both bisphenol F and its other analogs   .
BPF exposure significantly reduced the plasma GnRH, LH, testosterone, and FSH. BPF disrupted the physiological sequence of events along the hypothalamus-pituitary-testicular axis. Suppression of the hypothalamus-pituitary-testicular axis could significantly reduce the activity of GnRH secreting cells and, hence, the hormone's plasma level. The consequent weak stimulatory effect of GnRH on the anterior pituitary causes impaired secretion of FSH and LH and thus a significant reduction in testosterone. The reduced testosterone level could not instigate stimulatory positive feedback effects at the anterior pituitary and hypothalamic level to bring about a compensatory increase in the levels of GnRH and gonadotropins. These findings were similar to a previous study that reported a significant reduction in plasma testosterone, LH, and FSH following bisphenol F treatment  and may suggest that BPF induces a local toxic effect on the testis as suppression of the hypothalamus-pituitary-testicular axis.
BPF-induced suppression of steroidogenesis was associated with reduced steroidogenic enzymes, evidenced by the significant reduction in the activities of 3β-HSD and 17 β-HSD, which was accompanied by reduced testicular cholesterol, the precursor of testosterone. These observations corroborate previous findings , which reported similar observations following bisphenol A treatment. It is plausible to infer that BPF-induced impaired steroidogenesis was, at least in part, a consequence of BPF-induced downregulation of 3β-HSD and 17 β-HSD. Also, the reduced testicular cholesterol concentration may likely be due to impaired steroidogenic acute regulatory protein (StAR), responsible for cholesterol transportation to the inner mitochondrial membrane from the outer mitochondrial membrane.
Furthermore, BPF treatment significantly increases testicular lactate, LDH, and GGT and a significant reduction in testicular sorbitol dehydrogenase (SDH). The significant increase in testicular lactate could result from an observed increase in LDH. LDH is responsible for converting pyruvate to lactate during the anaerobic condition. It is important to note that there is no available data to compare our findings, but the significant increase in testicular LDH and lactate could be a compensatory adaptation to restore the observed BPF-induced testicular damage and oxidative stress. This agreed with previous study  that reported lactate to preserve germ cells by limiting the loss of spermatids and spermatocytes in rats. A primary index of Sertoli role is GGT, and its activity is parallel to Sertoli cell replication and maturation . The significant increase in the activity of testicular GGT in animals treated with BPF in this present study suggests a less effective function of the Sertoli cell. SDH activities provide glycolysis and oxidative phosphorylation energy by converting sorbitol to fructose to form ATP . The observed unignorable reduction in SDH in this study suggests that BPF-treatment might lead to an energy imbalance in the sperm cell.
The balance between the generation and scavenging reactive oxygen species (ROS) must be maintained under physiologic conditions. Under pathological conditions, excessive ROS are produced, altering the balance between ROS (pro-oxidants) production and removal (antioxidants). This condition is referred to as oxidative stress. In the testes of BPF administered animals, oxidative stress was noticed. This was made evidenced by a significant increase in the level of testicular MDA and a significant reduction in testicular CAT, GSH, GST, SOD, and GPx. The observed increase in pro-oxidant and decrease in antioxidants concurred with  and  with similar findings following administration of BPF and its analog.
In this present study, a significant increase in MPO, NO, TNF-α and IL-6 was observed after exposure to BPF. These findings is in agreement with a previous study , which reported a significant increase in pro-inflammatory markers after bisphenol-A administration. It is worthy to note that the significant increase in inflammatory markers could result from the increased generation of reactive oxygen species. The observed significant increase in testicular NO corroborates a previous study  that associated BPF treatment with a significant increase in NO. The significant increase in testicular NO may react with O2- to generate peroxynitrite, a potent oxidant that can decompose to produce reactive hydroxyl radical, which can eventually lead to testicular damage . The significant increase in testicular MPO might also contribute to the testicular toxicity observed in this study. This is in agreement with a study  that revealed that the MPO properties, which are autonomous of its enzymatic activity, and also oxidants that are MPO-derived, seem to take part in a series of events that assists the propagation and initiation of the inflammatory response and, as a result, are involved in tissue pathology in diseases depicted by oxidative stress and increase in inflammation.
The increase in XO and Uric acid could significantly increase ROS levels since XO and lipid peroxidation have been linked together . Although, it is important to note that UA may act as an antioxidant , the ability to curtail radical forming systems . The pro-oxidant activity of UA can result from its reaction with other oxidants to produce radicals that majorly target cellular . The lipophilic environment created due to the accumulation of lipids, in turn, creates an unfavourable environment for the antioxidant activity of UA , and the uric acid is thereby converted to oxidants by the oxidized lipids . The finding that BPF treatment significantly increased testicular uric acid level suggests that its toxic effect on the testis could be due to the accumulation of uric acid. The significant increase in testicular UA may result in the activation of a pro-inflammatory response , resulting in a significant increase in testicular NO and MPO activity. Also, it may result in the observed oxidative stress following BPF treatment through increased generation of reactive oxygen species . Since BPF could stimulate both pro-inflammatory signalling and oxidative stress, it is logical to conclude that BPF mediates its gonadotoxic effect via XO/UA-dependent oxidative stress and inflammatory response.
Probing the mechanism behind BPF-induced oxido-inflammatory damage to the testis and investigating its effects is important in understanding the aetiopathogenesis of the observed testicular toxicity. Our observations that BPF-induced oxidative and inflammatory damage to the testis is accompanied by a significant increase in DNA fragmentation, a marker of apoptosis. This finding concurred with a previous study that observed that a significant increase in UA stimulates epithelial-to-mesenchymal transition and apoptosis through oxidative stress-driven inhibition of E-cadherin synthesis and promotes E-cadherin degradation . BPF exposure-induced testicular toxicity may be associated with the observed oxido-inflammatory response and apoptosis. Hence, BPF-induced testicular toxicity may be multifaceted; upregulation of XO/UA signaling may promote oxidative stress and inflammatory response, which are triggers of apoptosis  .Taken together, BPF exposure is a potential risk factor for testicular injury mediated by the upregulation of XO/UA signalling and DNA fragmentation.
Surprisingly, BPF withdrawal did not reverse the observed disruptive effect of BPF on the testis. The testicular toxicity of BPF lingers beyond expectation, evidenced by unrestored testicular homeostatic balance within 28 days of BPF withdrawal. It is expected that withdrawal of BPF for 28 days would ameliorate BPF-induced gonadotoxicity; astonishingly, it did not. This may be due to its high affinity for fatty tissues. Bisphenols can accumulate in fatty tissues  such as the testis, thus exerting a prolonged effect even after cessation of exposure.