Emerging evidence suggests that environmental toxicants may influence inflammation-promoted chronic disease susceptibility during early life. BPA, an environmental endocrine disruptor, can transfer across the placenta and accumulate in fetal gut and liver. However, underlying mechanisms for BPA-induced colonic and liver inflammation are not fully elucidated. In this report, we show how perinatal BPA exposure in rabbits alters gut microbiota and their metabolite profiles, which leads to colonic and liver inflammation as well as to increased gut permeability as measured by elevated serum lipopolysaccharide (LPS) levels in the offspring. Also, perinatal BPA exposure leads to reduced levels of gut bacterial diversity and bacterial metabolites (short-chain fatty acids [SCFA]) and elevated gut permeability—three common early biomarkers of inflammation-promoted chronic diseases. In addition, we showed that SCFA ameliorated BPA-induced intestinal permeability in vitro. Thus, our study results suggest that correcting environmental toxicant-induced bacterial dysbiosis early in life may reduce the risk of chronic diseases later in life.

We evaluated sequelae to early exposure of male rabbits to drinking water containing chemicals typical of ground water near hazardous waste sites. The mixture (p.p.m. at 1x) was 7.75 arsenic, 1.75 chromium, 9.25 lead, 12.5 benzene, 3.75 chloroform, 8.5 phenol and 9.5 trichloroethylene. Dutch-Belted does received mixture at 0x (deionized water; control), 1x or 3x as drinking water from day 20 pregnancy through weaning. Exposure of individual males (7-9/treatment) continued until 15 weeks (adolescence); then, all males received deionized water. At 57-61 weeks of age, ejaculatory capability and seminal, testicular, epididymal and endocrine characteristics were evaluated. At 10 opportunities with a female teaser, all seven control males ejaculated every time, but 12 of the 17 treated males failed to express interest, achieve erection and/or ejaculate on one to five occasions; four of the 12 accomplished ejaculation with a second male teaser. Total spermatozoa/ejaculate and daily sperm production were unaffected. However, treatment caused (P < 0.03) acrosomal dysgenesis and nuclear malformations. Baseline serum concentrations of LH were lower, but with borderline significance (P = 0.05). Testosterone secretion after exogenous human chorionic gonadotrophin (P < 0.04) was low. Thus, even at 45 weeks after last exposure to drinking water pollutants, mating desire/ability, sperm quality, and Leydig cell function were subnormal.

Unlike seminomas in humans, seminomas in animals are not typically sub-classified as classical or spermatocytic types. To compare testicular germ cell tumours (TGCT) in dogs with those of men, archived tissues from 347 cases of canine testicular tumours were morphologically evaluated and characterized using human classification criteria. Histopathological and immunohistological analysis of PLAP, KIT, DAZ and DMRT1 expression revealed that canine seminomas closely resemble human spermatocytic seminomas. In addition, a relatively frequent concomitant presence of somatic cell tumours was noted in canine TGCT. None of the canine TGCT evaluated demonstrated the presence of carcinoma in situ cells, a standard feature of human classical seminomas, suggesting that classical seminomas either do not occur in dogs or are rare in occurrence. Canine spermatocytic seminomas may provide a useful model for this rare human neoplasm.

We studied sequelae of prenatal plus infantile exposure of male rabbits to vinclozolin, because it is ingested by women and children. Female Dutch-Belted rabbits (7 -10/group) were treated daily per orum from gestation day 15 through post-natal week 4 to provide 0, 7.2, or 72 mg vinclozolin/kg dam's body weight/day. Vinclozolin had no effect on maintenance of pregnancy, growth of pups, age at testicular descent or weight of organs. Concentrations of serum LH or testosterone at 6, 12, or 24 weeks of age were unaffected. However, FSH was lower (P < 0.05) in both vinclozolin groups at all three ages. Following injection of GnRH at 12 or 24 weeks, the increase in FSH was less (P < 0.05) in both vinclozolin groups, as was testosterone at 12 weeks of age. After full sexual maturity, 2 of 7 low dose rabbits were uninterested in female or male teasers and never achieved erection or ejaculation. Overall, rates of ejaculation failure were: control 0% (0/48), low dose 29% (12/42), and high dose 5% (3/60). Daily sperm production per gram of testis and total number of sperm per ejaculate in both vinclozolin groups were similar (P > 0.1) to controls. However, semen from vinclozolin rabbits contained over two times more (P < 0.05) morphologically abnormal spermatozoa, mostly nuclear and acrosomal defects, than semen from controls. Seminiferous tubules with degenerative changes were more frequent (P < 0.05) in vinclozolin rabbits than in controls. Lesions included syncytia of spherical spermatids and desquamation of germ cells. Hence, developmental exposure to vinclozolin caused presumably permanent changes in copulatory ability, secretion of FSH, and spermiogenesis.

Four groups (minimum of 10/dose group) of male Dutch-belted rabbits were treated daily with dibromoacetic acid (DBA) via drinking water beginning in utero from gestation day 15 to adulthood; target dosages were 1, 5, and 50 mg DBA/kg body weight. Developmental, prepubertal as well as postpubertal reproductive sequelae were evaluated. One (out of 22), 2 (out of 32), and 1 (out of 21) male offspring in the 1, 5, and 50 mg DBA/kg groups were unilaterally cryptorchid. There were no significant differences in serum follicle-stimulating hormone, luteinizing hormone, and testosterone (basal concentrations or in response to exogenous gonadotropin-releasing hormone) in both prepubertal and adult rabbits. Chronic exposure to DBA adversely affected the mating abilities of some rabbits. The number of sperm produced was not affected, but spermiogenesis was disrupted, resulting in unique sperm acrosomal-nuclear malformations even at the 1-mg dose level. Concentrations of SP22, a specific sperm membrane fertility protein, in detergent extracts of ejaculated sperm were significantly lower (P , .05) in all DBA-treated groups compared with controls. The conception rates following artificial insemination of a constant number of sperm for 1, 5, and 50 mg DBA/kg groups were 55% (10/ 18), 65% (13/20), and 55% (9/16), respectively, vs 85% (17/20) for control group. Histologic lesions in testes characterized by spermatogenic arrest predominantly at the round spermatid stage, pyknosis of differentiating germ cells, and ultimate degeneration and desquamation leaving focal vacuolation in seminiferous epithelium were evident in DBA-treated groups. Thus, male rabbits exhibit reproductive toxicity with exposure to DBA during reproductive development at dosages as low as 1 mg/kg body weight.