Development of testicular lesions in F344 rats after treatment with boric acid

Treinen, Kimberley A.; Chapin, Robert E.

doi:10.1016/0041-008x(91)90212-w

Cited by 72 publications

(40 citation statements)

References 21 publications

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“…This lesion has been seen for some other toxicants, but no satisfactory molecular target or mechanism has been proposed or demonstrated. The lack of consistent effects on testosterone was frustrating, although others have documented some changes (5,10), and both these reports are of similarly small changes in testosterone levels. Our conclusion is that there may well be a depression of circulating testosterone at these elevated boron levels, but it requires serial blood samples from cannulated rats to be identified (10).…”

Section: Discussionmentioning

confidence: 97%

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The reproductive toxicity of boric acid.

Chapin

1994

Environ Health Perspect

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Previous studies on the reproductive toxicity of boric acid have indicated that male rodents suffer testicular atrophy after treatment. There were, however, no studies of the potential effects on female fertility or on the neonate. In addition, no study described the development of the testicular lesion, thought to be related to the mechanism of toxicity. A Reproductive Assessment by Continuous Breeding (RACB) study using mice exposed to boric acid at 1000, 4500, and 9000 ppm in the diet indicated that there are probably multiple sites of action, although male fertility appears very sensitive. Possible effects on female fertility cannot be separated from potential developmental toxicity and need additional investigation.Decrements in sperm motility were observed at all exposure levels, and testicular atrophy was confirmed in high-and middle-dose-group males.This was investigated further by timed serial-sacrifice studies using 9000 ppm in the diet of rats, which found that the first lesion seen in the testis was an inhibition of spermiation (release of mature spermatids). With continued dosing, this was followed by a disorganization of the normal ordered layering of the seminiferous epithelium, germ cell sloughing and death, and finally, atrophy. Subsequent studies using additional doses (2000, 3000, 4500, 6000, and 9000 ppm) found that it was possible to observe inhibited spermiation that did not progress to atrophy (4500 ppm and below) within the 9-week exposure period. Also, once atrophic (from 9000-and 6000-ppm exposures), there was no return of spermatogenesis after refeeding of normal diet for 8, 16, 24, or 32 weeks, despite the presence of a normal-sized population of spermatogonia that was seen to divide. No effects were observed in rats treated with 2000 ppm. Testicular boron concentrations remained steady during exposure at the same level as found in blood, and declined to background levels within 72 hr after cessation of exposure. Bone boron levels were greater than those found in blood, and maintained slightly elevated levels even 32 weeks after the cessation of exposure. These studies document the effects of boric acid on functional and structural aspects of the male reproductive system; demonstrate that the tissue concentration of boron, and not total dose, is important for the testicular toxicity; and show that there is a threshold for these effects. These studies also suggest that the potential for recovery from boric acidinduced testicular atrophy should be examined in other species to evaluate the significance of the persistent atrophy seen in the rats. -Environ Health Perspect 102(Suppl 7): 87-91 (1994)

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Section: Discussionmentioning

confidence: 97%

“…This study was performed to define the steps in the development of the testicular lesion (5). Several small pilot studies were performed to ascertain that boric acid would affect rats, and to estimate appropriate sacrifice times.…”

Section: Male Pathogenesis Studymentioning

confidence: 99%

The reproductive toxicity of boric acid.

Chapin

1994

Environ Health Perspect

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“…High-dose boric acid exposure produces testicular lesions in adult rats characterized by inhibited spermiation (IS) that may progress to nonrecoverable atrophy, depending on the dose (1)(2)(3)(4). The mechanism for the apparent selective testicular toxicity of boric acid remains obscure, and has not been thoroughly studied.…”

Section: Introductionmentioning

confidence: 99%

“…One mechanism could be decreased testosterone. Rats fed boric acid exhibited slightly reduced basal serum testosterone levels, and secretagogue challenge studies suggested that the decrease was CNSmediated (1,5). These data are relevant because IS is thought to reflect a change in hormone status (6), although other processes likely are involved.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the testicular toxicity of boric acid in rats: in vivo and in vitro studies.

Chapin²

1994

Environ Health Perspect

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High-dose boric acid (BA) exposure produces testicular lesions in adult rats characterized by inhibited spermiation (IS) that may progress to atrophy. In vivo and in vitro studies addressed possible mechanisms. In vivo, boron tissue disposition was examined, since no detailed data existed, and relevant boron concentrations for in vitro studies needed to be set. Since BA induces riboflavinuria and also affects calcium/phosphorus homeostasis, and testis zinc appears essential for normal testis function, we examined BA effects on flavin status and testis levels of phosphorus (P), calcium (Ca) and zinc (Zn). Data showed that the testicular toxicity and central nervous system (CNS) hormonal effect were not due to selective boron accumulation in testis or brain/hypothalamus, with testis boron concentrations at approximately 1 to 2 mM; that riboflavin deficiency is not involved, due to both the absence of overt signs of deficiency and effects on tissue flavin content during BA exposure; and that changes in testis P, Ca and Zn levels did not precede atrophy, and are therefore unlikely to be mechanistically relevant. In vitro studies addressed the hallmarks of the BA testicular toxicity: the mild hormone effect, the initial IS, and atrophy. No effect of BA on the steroidogenic function of isolated Leydig cells was observed, supporting the contention of a CNS-mediated rather than a direct hormone effect. Since increased testicular cyclic adenosine monophosphate (cAMP) produces IS, and a role for the serine proteases plasminogen activators (PAs) in spermiation has been proposed, we examined in vitro BA effects on both Sertoli cell cAMP accumulation and PA activity, respectively. Results showed that the IS is not due to BA effects on either process. To address the atrophy, we evaluated BA effects in Sertoli-germ cell cocultures on: Sertoli cell energy metabolism, since lactate, secreted by Sertoli cells, is a preferred energy source for germ cells; and also on DNA/RNA synthesis, since germ cells synthesize DNA/RNA and BA impairs nucleic acid synthesis in liver, and may do so in testis. The most sensitive in vitro endpoint was DNA synthesis of mitotic/meiotic germ cells, with energy metabolism in Sertoli or germ cells affected to a lesser extent. The in vitro effect on DNA synthesis was manifest in vivo as a decrease in the early germ cell/Sertoli cell ratio prior to atrophy in testes from BA-exposed rats. Overall, these combined studies revealed some changes offering a plausible explanation for the atrophy aspect of the BA testicular lesion. However, the mechanism for the IS is still undefined, and should be the subject of future work. -Environ Health Perspect 102(Suppl 7): 99-105 (1994)

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“…After subchronic exposure, the histopathological effects range from inhibition of spermiation (Linder et al, 1990;Treinen & Chapin, 1991), to the degeneration of the seminiferous tubules, with a variable loss of germ cells, even reaching the complete absence of them. Atrophy and reversible or irreversible loss of fertility may result.…”

Section: Introductionmentioning

confidence: 99%

Boron as Testicular Toxicant in Mice (Mus domesticus)

Bustos‐Obregón

Olivares

2012

Int. J. Morphol.

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SUMMARY:It has been reported that boron causes changes in various systems, including the male reproductive system. Residents in some towns in northern Chile were consuming a few years ago in the drinking water 20 times more than the amount established as permissible limit by WHO. This study evaluates the effects in an animal model of high intake of boron on the testis. Boron was administered in the drinking water. Twenty male mice (Mus domesticus), sexually mature, were used, divided into 2 groups: the experimental group was given Boron at a dose of 12 mg/L, and the control group 0.6 mg/L, for 42 days. Sections of testis were obtained for: HE staining (Morphometry and Histopathology), Immunohistochemistry (Cox-2), Mallory and Picrosirious stain (evaluation of tunica albuginea). The results indicate that ingestion of a dose of 12 mg Boron/L produces vacuolization, tubular epithelial desquamation and tamponade. Morphometry revealed decreased tubular diameter and epithelial height and lumen diameter and increased interstitial area in the exposed group. Immunodetection of COX-2 was positive in high percentage of tubules in the intoxicated group. The tunica albuginea was thinner, with decreased percentage of type I collagen fibers and an increase in the percentage of type III collagen fibers in animals exposed to boron in contrast to the control group. Exposure to critical levels of boron produces severe histopathological changes in the testis, altering morphometric parameters and causing overexpression of Cox-2. Finally, evaluation of collagen fibers suggests that Boron produced a degradation of the collagen of the tunica albuginea, causing a decrease in the thickness of it and altering the percentage ratio collagen I/collagen III, a process called collagenolysis.

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Development of testicular lesions in F344 rats after treatment with boric acid

Cited by 72 publications

References 21 publications

The reproductive toxicity of boric acid.

The reproductive toxicity of boric acid.

Mechanism of the testicular toxicity of boric acid in rats: in vivo and in vitro studies.

Boron as Testicular Toxicant in Mice (Mus domesticus)

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