Prenatal Exposure to Environmental Concentrations of Organochlorines Impede Male Fertility and Subsequent Embryo Development in the Rat.

Elevated levels of organochlorines, including pesticides and industrial compounds, some of which are known endocrine disruptors, have been reported in human and wildlife populations worldwide. To test the hypothesis that prenatal exposure to organochlorines contaminating the Far North adversely affects reproductive development and function, we developed an experimental rat model. Sprague-Dawley females were gavaged thrice weekly for five weeks with environmentally-relevant concentrations (500 µg PCB/kg body weight/day) of an organochlorine mixture, resembling that found in seal blubber, or corn oil (control). Rats were then mated to untreated males and gavagedthough gestation. We obtained 31 F1 organochlorine males and 33 F1 control males; after weaning, all F1 males were fed commercial rat chow and never directly exposed to organochlorines themselves. In support of our hypothesis, 16% of the F1 organochlorine males retained residual nipples whereas none were apparent on the F1 control males (P = 0.07). Also, prenatally-exposed F1 pups underwent puberty earlier than controls (P < 0.05). To assess fertility and the ability to sire normal offspring (F2 generation), at 90 days of age, 15 F1 control and 15 F1 organochlorine males were each mated to 2 untreated females. At 19.5 days of gestation, foetuses from each female were analysed. Fourteen percent of the F2 foetuses from the prenatally-exposed F1 organochlorine fathers had gross abnormalities, including situus ambigus and cryptorchidism, whereas none of the controls were abnormal. Litter sizes from prenatally-exposed F1 organochlorine fathers were approximately 20% smaller than those from F1 controls (P < 0.05) and, surprisingly, contained fewer male pups than control litters (P = 0.06). More unfertilized oocytes and/or preimplantation embryo loss occurred in females mated to prenatally-exposed F1 males (3.8/female) than when mated to F1 controls (1.0/female) (P < 0.05). Together, these results suggest that prenatal organochlorine exposure reduces sperm function resulting in lower fertility and/or comprised embryo developmental competence. Following these initial observations, we analysed the reproductive organs and sperm quality of the F1 males at 180 days of age. Prenatally-exposed F1 males had smaller epididymides and prostates than F1 controls (P < 0.05). Although prenatally-exposed F1 males had more motile and progressively motile sperm after 2 h incubation at 37°C than F1 controls (P < 0.05), the F1 organochlorine sperm were less able to undergo capacitation in vitro (chlortetracycline fluorescent pattern B) than F1 control sperm (P < 0.05). Susceptibility of sperm DNA to denaturation, assayed by SCSA and acridine orange, were not apparent, however, the TUNEL assay revealed more single- and double-strand DNA breaks in sperm from the prenatally-exposed and control F1 males, perhaps reflecting improper chromatin packaging. In function of these results, it appears that a major impact of prenatal exposure to an environmentally-relevant concentration of organochlorines is through endocrine disruption, resulting in impaired sperm maturation and function. In addition, it is tempting to speculate that the male germ cell epigenome is modified due to prenatal organochlorine exposure, which could contribute to early embryo loss and abnormalities of foetal development. Experiments to test this new hypothesis are currently underway. Financed by FQRNT. (poster)

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