Table 2.
Summary of experimental studies on multigenerational and transgenerational (F1–F3) effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on male (M) and female (F) offspring. Reported changes statistically significant unless indicated nonsignificant (ns).
| A. Rodent studies: both paternal and maternal exposure | ||||||
| Species, Strain | Exposure to TCDD | Effects | Reference | |||
| Dose | Timing | F1 Generation | F2 Generation | F3 Generation | ||
| Rat, Sprague Dawley | 0.001, 0.01 or 0.1 µg/kg bw/day, in diet | 90 days prior to mating throughout 3 generations (continuous exposure) | 0.001 µg/kg: slightly dilated renal pelvis ↑, 0.01 µg/kg: time from cohabitation to delivery ↑, fertility ↓, postnatal survival ↓, 0.1 µg/kg: fertility ↓, litter size ↓, gestation survival index ↓ (discontinued) |
0.001 µg/kg: no effects, 0.01 µg/kg: body weight ↓, time from cohabitation to delivery ↑, fertility ↓, litter size ↓, gestation survival index ↓, postnatal survival ↓ |
0.001 µg/kg: no effects, 0.01 µg/kg: body weight ↓, litter size ↓, gestation survival index ↓ |
Murray et al., 1979 [101] |
| Rat, Sprague Dawley | 0.001, 0.01, or 0.1 µg/kg bw/day, in diet | 90 days prior to mating throughout 3 generations | Male/female ratio not changed | Male/female ratio not changed | Male/female ratio not changed | Rowlands et al., 2006 [110] (re-examination of the Murray et al. 1979 data 99]) |
| Rat, Sprague Dawley | 100 ng/kg/day ip in DMSO Total dose: 700 ng/kg/day |
GD 8-14 | M: delayed puberty onset; testis weight ↑, prostate and kidney weight ↓ F: pubertal abnormalities; body weight ↓, ovarian primordial follicles ↓, polycystic ovary disease |
Not examined | M: delayed puberty onset; kidney: weight ↓, fluid filled cysts, glomerular size ↓, thickening of Bowman’s capsule; serum testosterone ↑, 50 differentially methylated regions in sperm DNA, atrophic prostate duct epithelium F: early onset of puberty, kidney weight ↓, ovarian primordial follicles ↓, polycystic ovary disease |
Manikkam et al., 2012a,b [111,112]; Nilsson et al., 2012 [113] |
| Rat, Sprague Dawley | 100 ng/kg/day ip in DMSO Total dose: 700 ng/kg/day |
GD 8-14 | F: ovarian primordial follicles ↓, polycystic ovary disease: small ovarian cysts ↑ (ns), large ovarian cysts ↑ (ns) | Not examined | F: ovarian primordial follicles ↓, polycystic ovary disease: small ovarian cysts ↑, large ovarian cysts ↑ (ns) | Nilsson et al., 2012 [113] |
| B. Rodent studies: paternal or maternal exposure | ||||||
| Mouse, C57Bl/6 | 10 µg/kg, single dose, oral gavage in corn oil | GD 15.5 TCDD exposed F1 and F2 females mated with unexposed males |
F: fertility ↓, premature births ↑, progesterone receptor immunostaining in uterus of infertile mice ↓, sensitivity to inflammation ↓ | F: fertility ↓, premature births ↑ | F: fertility ↓, premature births ↑ (in F4: progesterone receptor immunostaining in uterus of infertile mice ↓) |
Bruner-Tran and Osteen, 2011 [114] |
| Mouse, C57Bl/6 | 10 µg/kg, single dose, oral gavage in corn oil | GD 15.5 TCDD exposed F1 and F2 males mated with unexposed females |
M: fertility ↓ (47% pregnant), premature births in unexposed partners ↑, sperm concentration ↓, normal sperm morphology ↓, sperm AHR expression ↑, testicular inflammation and apoptosis ↑ | M: fertility ↓ (48% pregnant), premature births in unexposed partners ↑, normal sperm morphology ↓, sperm AHR expression ↑, testicular inflammation and apoptosis ↑ | M: fertility ↓ (50% pregnant), premature births in unexposed partners ↑, normal sperm morphology ↓, sperm AHR expression ↑, testicular inflammation and apoptosis ↑ | Bruner-Tran et al., 2014 [115] |
| Mouse, C57Bl/6 | 10 µg/kg, single dose, oral gavage in corn oil | GD 15.5 TCDD exposed F1 and F2 males mated with unexposed females |
Placental weight ↓, pup weight ↓ F: 15% of genes in placenta differentially methylated, hypermethylation of progesterone receptor (Pgr), hypomethylation of insulin-like growth factor-2 (Igf2, ns), mRNA of Pgr-b, Pgr-a/b, Igf-2, and H19 ↓, IGR2 protein ↓, mRNA of DNA methyltransfereases ↑ Dnmt1, Dnmt3a (ns), Dnmt3b (ns) M: in sperm hypermethylation of Pgr, hypomethylation of Igf2 |
Not examined | Placental weight ↓, pup weight ↓ F: 15% of genes in placenta differentially methylated, hypermethylation of Pgr, hypomethylation of Igf2 (ns). M: in sperm hypermethylation of Pgr (ns) and hypomethylation of Igf2 (ns), mRNA of Pgr-b, Pgr-a/b (ns), Igf-2 (ns) and H19 ↓, IGR2 protein ↓, mRNA of DNA methyltransfereases ↑ Dnmt1, Dnmt3a (ns), Dnmt3b (ns) |
Ding et al., 2018 [116] |
| Rat, Wistar | 0.1, 0.5 or 1.0 µg/kg bw, single dose, oral gavage in corn oil | GD15 TCDD exposed F1 and F2 males mated with unexposed females |
M: serum testosterone ↓ (dose-dependent, only 1.0 significant), sperm transit time ↓ (ns), normal sperm morphology ↓ (0.5 and 1.0) F: implants per corpora lutea ↓ in unexposed partners at 0.5 and 1.0 µg/kg bw: Ctr 75.2%, 0.5 62.0%, 1.0 58.7% |
F: implants per corpora lutea ↓ in unexposed partners at 0.1, and 1.0 µg/kg bw: Ctr 61.9%, 0.1 41.1%, 0.5 50.5% (ns), 1.0 43.6% | F: implants per corpora lutea ↓ in unexposed partners at 0.1, 0.5 and 1.0 µg/kg bw: Ctr 82.4%, 0.1 50.7%, 0.5 56.6%, 1.0 31.8% | Sanabria et al., 2016 [117] |
| C. Zebrafish studies | ||||||
| F0 generation | F1 generation | F2 generation | ||||
| Zebrafish | 20 µg/kg in diet | Parental exposure 47 days | No effect on global DNA methylation in liver, CYP 1A1 ↑ | No effect on global DNA methylation in liver | Olsvik et al., 2014 [118] | |
| Zebrafish AB strain |
50 pg/mL in water (dissolved in DMSO) | 1 h at week 3 and week 7 post fertilization | Male/female ratio ↓ (Ctr 71.1%, TCDD 55.5%) F: atretic ovarian follicles (65.5%), egg release ↓, fertilization success ↓ Skeletal abnormalities (82.4%) axial kinks (54.5%) cranial malformations (46.9%) jaw malformations (34.5%) |
Male/female ratio ↓ (Ctr 70.8%, TCDD 59.3%) F: atretic ovarian follicles (46.1%), egg release ↓ M: elicitation of egg release ↓, fertilization success ↓ Skeletal abnormalities (34.9%) axial kinks (28.1%) cranial malformations (11.7%) jaw malformations (3.7%, ns) |
Male/female ratio ↓ (Ctr 78.7%, TCDD 61.4%) F: atretic ovarian follicles (7.7%, ns) M: elicitation of egg release ↓, fertilization success ↓ Skeletal abnormalities (22.1%) axial kinks (17.3%) cranial malformations (7.8%, ns) jaw malformations (0.9%, ns) |
Baker et al., 2014 [119] |
| Zebrafish AB strain |
50 pg/mL in water (dissolved in DMSO) | 1 h at week 3 and week 7 post fertilization | M: in testis 722 differentially expressed genes | M: in seminiferous tubules spermatogonia ↑, spermatozoa ↓, in testis 634 differentially expressed genes | M: in seminiferous tubules spermatozoa ↓ (ns), in testis 1105 differentially expressed genes | Meyer et al., 2018 [120] |