Embryotoxic effects of thalidomide-derivatives in the non-human primate Callithrix jacchus

Abstract

The response of pregnant marmosets (Callithrix jacchus) to the thalidomide derivative EM 12 was evaluated. EM 12 was selected for these studies because it is more active than thalidomide and is much more stable for hydrolysis. Skeletal gross structural abnormalities were observed when EM 12 was given to marmosets for 3-7 days during the period between days 49 and 60 post ovulation. Using the treatment schedule finally adapted in our laboratory, i.e. treatment during days 51-57 post ovulation, doses of 5 (or 10) mg EM 12/kg body wt induced the typical limb abnormalities known from man with an 80-100% certainty. In some animals we could observe the typical pattern of abnormalities even with doses as low as 1 mg EM 12/kg body wt. Abnormalities of the skeleton induced during this sensitive period are described. None of these (except some bifurcations of ribs) were seen in any of the ten litters (23 fetuses) serving as controls during the period of the study.

Thalidomide‐induced teratogenesis: History and mechanisms

“…Early exposure resulted in severely truncated limbs, even Amelia, whereas later exposure caused less severe damage, for example loss of a digit or digit tips. In fact the damage caused by CPS49 in chicken embryos was consistent with damage seen in other studies using thalidomide (Somers, 1962; Boylen et al, 1963; Merker et al, 1988; Tamilarasan et al, 2006; Therapontos et al, 2009; Vargesson, 2009, 2013; Ema et al, 2010). …”

“…Mice, traditionally used to screen for drug action, are less sensitive to thalidomide than other species like non‐human primates, rabbits, etc. (Merker et al, 1988; Stephens et al, 2000; Vargesson, 2013). Why mice are less sensitive to the drug remains unclear.…”

“…Animal studies, particularly in nonhuman primates, show that following thalidomide exposure a range of damage is induced, which can vary between each of the litter‐mates (Merker et al, 1988; Ema et al, 2010; Vargesson, 2013). For example, one littermate could exhibit varying damage to all 4 limbs, another to one limb, and another just a tail anomaly (Merker et al, 1988; Ema et al, 2010; Vargesson, 2013).…”

“…For example, one littermate could exhibit varying damage to all 4 limbs, another to one limb, and another just a tail anomaly (Merker et al, 1988; Ema et al, 2010; Vargesson, 2013). The mechanism underlying this variance in damage is unknown, but also hints that thalidomide damage in humans could be broader.…”

Qualitative De Novo Analysis of Full Length cDNA and Quantitative Analysis of Gene Expression for Common Marmoset (Callithrix jacchus) Transcriptomes Using Parallel Long-Read Technology and Short-Read Sequencing

“…The teratogenic effects of some compounds have been shown to differ significantly between rodent and primate species. For example, whereas rodents are not sensitive to the teratogenic action of thalidomide analogues, the common marmoset is sensitive to these compounds [7]–[9].…”