699: Transgenerational alteration of estrus cycle proportion in F1 female mice obtained from F0 males neonatally exposed to 17α-hydroxyprogesterone caproate

Abstract

The FDA has approved 17α-hydroxyprogesterone caproate (17OHPC), for the prevention of recurrent preterm birth. Altering the steroid hormone milieu during fetal development has potential long-term adverse consequences as observed with in utero diethylstilbestrol exposure. Recently, we reported that neonatal 17OHPC-exposure altered the periodicity of the estrus cycles with suppressed estrogen-responsiveness in uterine and vaginal transcriptome of adult mice. Our current objective was to evaluate the potential developmental and transgenerational effects of 17OHPC-exposure on female reproductive tract function. Neonatal mice (C57BL/6J) were given 5 daily SC injections (day 0-4) of 5 μg/pup or 50 μg/pup 17OHPC or 20 μL of vehicle (sesame oil) control (F0-mice). At 3 months of age, both male and female F0-mice (control, 5 μg or 50 μg 17OHPC-exposed) were mated with control mice to evaluate the reproductive abilities of F0-mice and to obtain F1-mice. At 3 months of age, the periodicity of the estrus cycle and reproductive organs were analyzed in both male and female F0 and F1-mice. Both male and female F0-mice were fertile. Neonatal exposure to 17OHPC altered the periodicity of the estrus cycle at 3 months of age in F1-female mice; however, tissue mass of the reproductive organs were not significant affected by neonatal exposure to 17OHPC in either male or female sex of F1-mice. Intriguingly, F1- mice showed effects of F0 paternal 17OHPC-exposure on the periodicity of the estrus cycle, which had a longer diestrus compared to control females. Paternal contribution to the transgenerational effects of 17OHPC-exposure on the function of the female reproductive in the next generation was elucidated. Developmental alteration of the progestogen milieu in male F0-mice can be transferred to the next generation female F1-mice. Further investigations are required in mice as well as in human to understand the potential multi-generational effects of 17OHPC-exposure.