Table 1.

Summary of human and experimental studies with a focus on paternally (versus maternally) mediated effects of dioxins on the next generation offspring. Reported changes statistically significant unless indicated nonsignificant (ns).

A. Human Studies
Population	Dioxin Exposure		Effects Mediated via Paternal or Maternal Germline			Reference
			Paternal Germline	Maternal Germline	Maternal and Paternal Germline
Seveso population	Serum TCDD concentrations Unexposed: ≤15 pg/g fat Exposed: >15 pg/g fat Fathers: median 96.5, range 2.8–26,400 pg/g fat Mothers: median 62.8, range 6.45–12,500 pg/g fat		Male/female ratio ↓: Unexposed 55.7%, exposed 43.6% Fathers <19 years at exposure: Male/female ratio ↓: Unexposed 53.5%, exposed 38.2%	Male/female ratio not changed: 54.5% (ns)	Male/female ratio ↓: 44.2%	Mocarelli et al., 2000 [98]
Russian pesticide producers	Serum TEQ concentration (mainly TCDD): Unexposed: not reported Exposed: median 243 pg/g fat, range 17–8520 pg/g fat		Male/female ratio ↓: Unexposed 51%, exposed 38%; higher exposed cohort with median 715 pg/g fat: 23%	Male/female ratio not changed (51%, ns)	Male/female ratio ↓: Unexposed 51%, exposed 40%	Ryan et al., 2002 [99]
New-Zealand phenoxy herbicide producers	Serum TCDD concentration back-calculated to time of offspring’s birth (4 categories): <4, 4–20, 20–100 and ≥100 pg/g fat		Male/female ratio ↓: TCDD <20 pg/g fat: 60% TCDD ≥20 pg/g fat: 47%	Male/female ratio not changed: TCDD <20 pg/g fat: 53% TCDD ≥20 pg/g fat: 68%, ns	No data	Mannetje et al., 2017 [100]
B. Experimental Studies
Species, Strain	Dosing of TCDD		Effects Mediated via Paternal or Maternal Germline			Reference
	Dose	Timing	Paternal Germline	Maternal Germline	Maternal and Paternal Germline
Rat, Sprague Dawley	0.1 µg/kg bw/day, in diet	12 months starting 90 days prior to mating, TCDD exposed F0 males and females mated with unexposed partners	Cross-mating study: No harmful effects on pregnancy or resorptions.	Cross-mating study: No harmful effects on pregnancy, resorptions ↑	Cross-mating study: Not examined	Murray et al., 1979 [101]
Rat, Holzman	Loading dose 400 ng/kg bw + maintenance doses 80 ng/kg bw/week Adipose tissue TCDD conc.: F0 dams GD 20: 1810, weaning: 840; F1 pups PND 28: ~480 pg/g wet weight	F0 females exposed 2 weeks before mating until end of lactation. TCDD exposed F1 males mated with unexposed females	F2: Male/female ratio ↓ (Ctr 52.2%, TCDD 38%).	Not examined	Not examined	Ikeda et al., 2005 [102]
Mouse, ICR	Loading dose 2 ng/kg bw + maintenance doses 5 × 0.4 ng/kg/bw/week or 2000 ng/kg bw + 5 × 400 ng/kg bw/week, oral gavage in sesame oil	5 weeks before mating, TCDD exposed males mated with unexposed females	F1: Male/female ratio ↓: Ctr 53.1%, TCDD 2/0.4: 48.8% (ns), TCDD 2000/400: 46.2%	Not examined	Not examined	Ishihara et al., 2007 [103]
Mouse, ICR	Loading dose 2000 ng/kg bw + maintenance doses 5 × 400 ng/kg bw/week, oral gavage in sesame oil	5 weeks before mating, TCDD exposed males mated with nonexposed females	Y-bearing/X-bearing sperm ratio ↓ (ns, Ctr: 2.68, TCDD: 2.36), sperm Sry DNA concentration ↓ (ns, Ctr 28.12, TCDD 25.80), male/female ratio of 2-cell embryos ↓ (Ctr: 53.95%, TCDD 47.92%)	Not examined	Not examined	Ishihara et al., 2010 [104]
Mouse, C57Bl/6	10 µg/kg bw, single dose, oral gavage in corn oil	GD 15.5 TCDD exposed F1 males mated with unexposed females and TCDD exposed F1 females mated with unexposed males	F: fertility ↓ (47% pregnant), premature births ↑ (Ctr 20 days, TCDD 18.5 days); placental weight ↓, pup weight ↓, placental progesterone receptor A and B ↓ and toll-like receptor-4 mRNA expression ↑, sensitivity to inflammation ↑	F: fertility ↓ (39% pregnant); premature births ↑, pup weight ↓, placental progesterone receptor A and B ↓ and toll-like receptor-4 mRNA expression ↑, sensitivity to inflammation ↑	F: fertility ↓ (0% pregnant)	Ding et al., 2011 [105]
Mouse, ICR	Epididymal sperm exposed to 0, 0.25, 25, or 2500 ng/mL in vitro	Incubation time 1 h	Sperm motility and viability concentration dependently ↓, acrosome-reacted spermatozoa ↑ at 25 and 2500 ng/mL, Y-spermatozoa survival concentration dependently ↓ at 25 and 2500 ng/mL, fertilization and early embryonic development in vitro ↓ at 25 and 2500 ng/mL, male/female ratio of 2-cell embryos dose-dependently ↓ at 0.25, 25, and 2500 ng/mL, male/female ratio of blastocysts concentration dependently ↓ at 25 and 2500 ng/mL	Not examined	Not examined	You et al., 2018 [106]