Male reproductive toxicity and b-luteinizing hormone gene expression in sexually mature and immature rats exposed to 2-bromopropane

Abstract

<jats:p> 1 The reproductive effects of 2-bromopropane (2-BP) in sexually mature and immature male Sprague-Dawley rats were investigated. The animals were randomly divided into three treatment groups and one control group each of which comprised six mature and six immature rats. The treated groups were injected s.c. 200, 600 and 1800 mg/kg of 2-BP on 5 days a week for 5-7 weeks and the control group received the vehicle. 2 The absolute and relative testis weights were significantly reduced in 600 and 1800 mg/kg b.w. dose groups in both mature and immature rats. The absolute epididymis, prostate, seminal vesicle, and pituitary weights and the relative epididymis weights, however, were significant only at the highest dose level used in both mature and immature rats. 3 The sperm concentration and sperm viability in epididymal duct decreased and the percentage of abnormal sperm increased in a dose-dependent manner in both mature and immature rats. Additionally, serum testosterone level was significantly decreased in all dose groups in mature rats, and was significantly reduced only in the group treated with the middle and highest dose in immature rats. 4 In both mature and immature rats treated with 200 and 600 mg/kg, the seminiferous tubules were atrophied and all types of germ cells were decreased in number. At the highest dose level, the effect was more marked showing severely atrophied seminiferous tubules and a complete loss of all types of germ cells. 5 The mating, pregnancy and fertility indices were significantly reduced in the 600 and 1800 mg/kg groups. Additionally, at the highest dose group the number of implantations and viable fetuses per litter were reduced and the resorption rate was increased significantly. 6 In the mature rats, the b-LH gene expression increased significantly in the 1800 mg/kg group when compared to the control group. 7 It can be concluded that 2-BP induces alterations in both neuro-endocrine axis and the reproductive tract under the present experimental conditions. The no observed adverse effect level (NOAEL) in this study could be estimated to be lower than 200 mg/kg/b.w. based on the alteration in testicular morphology as well as on sperm parameters observed at the dose level of 200 mg/kg. </jats:p>

NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of 2-bromopropane

“…Evaluations conducted after i.p. [25] or s.c. [37] dosing provided evidence for altered Sertoli cell structure, Leydig cell hyperplasia, and decreased serum testosterone. Further histologic studies showed that 2-BP specifically kills spermatogonia, at least after short-term exposure to high doses [38,40].…”

“…Inhalation exposure of rats to ≥300 ppm (1509 mg/m 3 ) for at least 9 weeks resulted in atrophy of seminiferous tubules, reductions in germ cell numbers, and hyperplastic Leydig cells [22,26] in addition to reduced sperm counts and motility with increased numbers of abnormal sperm [22]. Although inhalation is the primary route of human exposure, testicular lesions, sperm effects, and/or Leydig cell hyperplasia were also observed in animal studies with i.p., s.c., or oral exposure [25,37,43]. Although limited, a s.c. injection study in male rats treated with ≥600 mg/kg bw 2-BP for 5 weeks demonstrated reductions in mating and fertility [37].…”

“…Although inhalation is the primary route of human exposure, testicular lesions, sperm effects, and/or Leydig cell hyperplasia were also observed in animal studies with i.p., s.c., or oral exposure [25,37,43]. Although limited, a s.c. injection study in male rats treated with ≥600 mg/kg bw 2-BP for 5 weeks demonstrated reductions in mating and fertility [37]. A series of studies demonstrated that acute, high-dose, parenteral exposure to 2-BP causes apoptotic death of spermatogonia within 3 days of exposure [38,40,43,45].…”

“…Expression of ␤-luteinizing hormone gene was measured in mature rats and was found to be increased in rats treated with 1800 mg/kg bw. Based on testicular and sperm effects, the authors estimated Table 10 Major effects in reproductive toxicity study in Sprague-Dawley rats by Wu et al [37] Number/age group Dose (mg/kg bw/day)…”

“…Wu et al [37] conducted a reproductive toxicity study to obtain information about 2-BP toxicity in mature (9-weekold) and immature (5-week-old) male Sprague-Dawley rats (Sino-British SIPPR/BK Animal Co.). Six rats/dose/age group were injected s.c. with 0, 200, 600, or 1800 mg/kg bw 2-BP (99.6% purity), 5 days/week with treatment lasting for 5 and 7 weeks in mature and immature rats, respectively.…”