The value of mechanistic studies in laboratory animals for the prediction of reproductive effects in wildlife: Endocrine effects on mammalian sexual differentiation

Abstract

Abstract-Wildlife populations from contaminated ecosystems display a variety of reproductive alterations, including cryptorchidism in the Florida panther, small baculum in young male otters, small penises in alligators, sex reversal in fish, and altered social behavior in birds. The formation of biologically plausible hypotheses regarding disruption of reproduction in wildlife can be facilitated by mechanistic studies on laboratory animals. To this end, we are investigating the in vivo and in vitro effects of endocrine-disrupting toxicants in rodents. In vitro studies have used receptor binding and transfected cell assays to confirm the suspected mechanism of action, whereas in vivo rodent studies examine altered sexual differentiation. Antiandrogenic pesticides compete with the natural ligands for both rat and human androgen receptors, block androgen-induced gene expression in vitro and in vivo, delay puberty, reduce sex accessory gland size, and alter male rat sex differentiation. In contrast, xenoestrogens affect female central nervous system sex differentiation and fecundity without producing malformations or infertility in male offspring. Prenatal administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or the TCDD-like polychlorinated biphenyls produce yet another profile of effects in the offspring, reducing numbers of ejaculated sperm in male progeny and inducing urogenital malformations in females. Although phthalates are reported to be estrogenic in vitro, in vivo exposure causes developmental alterations that more closely resemble antiandrogenic activity. The mammalian data indicate that exposure to endocrine-disrupting chemicals produces effects that are pathognomonic for mechanisms by which they act. Mechanistic information derived from mammalian studies can enhance our ability to predict toxicant effects on reproduction in fish and wildlife.

Need for establishing integrated programs to monitor endocrine active compounds

“…Finally, laboratory experiments demonstrated that TBT is able to induce imposex in mollusks at environmentally realistic concentrations and in a concentration-dependent way [10,11]. The TBT example satisfies most of the criteria of Gray et al [12], for a cause-effect relationship between an EAC and observed effects in wildlife, in particular correlation between effect and exposure, presence of the same effect in related species, induction of a specific pathognomic effect, disappearance of the effect with chemical cleanup, and ability to replicate the effect in the laboratory using relevant concentrations of the suspected EAC. One criterion that is not fulfilled in the TBT example is the identification of the mechanism of action.…”

“…In addition, however, a weight-of-evidence approach will have to be used to reduce the level of uncertainty. Several investigators have proposed criteria which can help to make a case for causal inference and to evaluate whether wildlife populations have been affected by EACs [4,12,57,58]. An example of such criteria is provided by the work of Ankley and Giesy [60], who suggested the following criteria for establishing cause-effect relationships: (1) documentation of effects in individuals, (2) documentation of adverse effects in populations, (3) coherence between effects observed in populations vs. those in individuals, (4) identification of a plausible mechanism of action consistent with effects in individuals (possibly through laboratory studies-see above), (5) positive identification of specific contaminants operating through this mode of action (possibly by combined bioanalytics/chemical analytics-see above), (6) reasonableness of dose-response relationships, (7) evidence of the recovery of populations or individuals upon removal of the stressor.…”

“…These experiments establish effect threshold values, and they determine the rate of increase of the response in relation to EAC concentration. Further, laboratory studies are important to establish basic biological traits and response patterns to EAC exposure of the monitored species, e.g., knowledge of developmental patterns of endocrine systems, or recognition of sensitive periods during development [12]. Finally, laboratory studies are essential in studying the mixture issue, i.e., the combined effect of various substances with identical or different modes of endocrine action.…”

Workshop to identify critical windows of exposure for children's health: reproductive health in children and adolescents work group summary.

“…If this migratory process were impeded, the ultimate gametogenic potential of the gonad might be affected (19 (19,(21)(22)(23). Importantly, such effects would be permanent.…”

“…The classic example is the widely studied estrogenic drug diethylstilbestrol (DES). When given to pregnant women, DES produced a variety of reproductive effects in their offspring, most of which were not apparent until after puberty [for example, structural abnormalities of the cervix, uterus, and fallopian tubes, and increased risk for adenocarcinoma of the vagina in daughters (22)]. Inappropriate exposure to progesterone may also produce abnormal sexual differentiation.…”