Windows of sensitivity to toxic chemicals in the development of reproductive effects: an analysis of ATSDR’s toxicological profile database

Abstract

Development of the fetus is a complex process influenced by many factors including genetics, maternal health, and environmental exposures to toxic chemicals. Adverse developmental effects on the reproductive system have the potential to harm generations beyond those directly exposed. Here, we review the available literature in Agency for Toxic Substances and Disease Registry toxicological profiles related to reproductive-developmental effects in animals following in utero exposure to chemicals. We attempt to identify windows of sensitivity. In the discussion, we correlate the findings with human development. The endpoints noted are fertility, estrus, anogenital distance, sex ratio, spermatogenesis, and mammary gland development. We identified some windows of sensitivity; however, the results were hampered by chronic-exposure studies designed to detect effects occurring throughout developmental, including multi-generational studies. This paper demonstrates the need for more acute studies in animals aimed at understanding time periods of development that are more susceptible to chemically induced adverse effects.

Experimental Evidence of 2,3,7,8-Tetrachlordibenzo-p-Dioxin (TCDD) Transgenerational Effects on Reproductive Health

“…These strongly intertwined processes determine whether a gene is expressed or silenced, playing a crucial role in cell and tissue development, through complex mechanisms that can affect transcript stability, DNA folding, nucleosome positioning, chromatin compaction, and nuclear organization [101]. Legend: DMR = DNA methylated regions; Pgr = progesterone receptor; Igf2 = insulin-like growth factor 2; AMH = anti-Müllerian hormone; AMHR2 = anti-Müllerian hormone receptor type II; 1 -Rat, Sprague Dawley; TCDD 100 or 500 ng/kg/day, oral gavage in corn oil, GD 8-14 [66]; 2 -Rat, Sprague Dawley; TCDD 0, 30, 100, 300 or 1000 ng/kg, single dose, oral gavage in corn oil, GD 11 [67]; 3 -Mouse, C57Bl/6; TCDD 10 µg/kg, single dose, oral gavage in corn oil, GD 15.5 [64]; 4 -Rat, Sprague Dawley; TCDD 100 ng/kg/day IP injection in DMSO, GD 8-14 [54].…”

“…Particularly, there is evidence that mammals are highly vulnerable to the damaging effects of endocrine disruptors (EDs), especially during periods of increased susceptibility (i.e., windows of susceptibility). For the male and female reproductive systems, this includes crucial events, such as fertilization and chromosomal sex determination, the fetal period up to infancy, and puberty and adolescence [2,3].…”