Effects on rat reproductive development produced by antiandrogens: AOPs and transgenerational effects

Earl Gray
Senior Reproductive Toxicologist,
EPA, USA
Dr Gray discussed different examples of adverse effects of phthalates. He went on to focus on vinclozolin, stating that studies show that exposure with vinclozolin during androgen-dependent sexual differentiation causes adverse effects in male F1 rats (Gray et al 1994; 1999).
However, he echoed earlier reference to the findings of the 2005 Anway et al study (gestational vinclozolin exposure was found to induce epigenetic alterations that were transmitted from F1 to F2, F3 and F4 generations), stating that these findings have not been found in other laboratories and three published studies could not replicate the effects of vinclozolin on the testis or fertility in any generation. The EPA conducted its own study to determine if vinclozolin treatment induced epigenetic effects in male rat offspring. It found that vinclozolin treatment did not reduce F1 or F2 fertility, nor did it induce the epigenetic changes described in the Anway study. The effects that were found were not transmitted to F2 or F3 generations.
Dr Gray concluded that his concern about many published TGE studies is that they cannot or have not been reproduced. He summarised other issues with studies:
Statistical issues.
Litter effects from P0 to F3 generations – need to track the lineages.
Small sample sizes.
Questionable statistical analyses.
Effects not always consistent from generation to generation.
Are the effects truly adverse?
Biologically plausible epigenetic mechanisms linking in utero epigenetic effects to an adverse developmental effect.
Inter-animal variability in epigenetic measurements.
Are we measuring the ‘right’ epigenetic events?