This review describes pre- and postnatal development of the male reproductive system in humans and laboratory animals, and highlights species differences in the timing and control of hormonal and morphologic events. Major differences are that the fetal testis is dependent on gonadotropins in humans, but is independent of such in rats; humans have an extended postnatal quiescent period, whereas rats exhibit no quiescence; and events such as secretion by the prostate and seminal vesicles, testicular descent, and the appearance of spermatogonia are all prenatal events in humans, but are postnatal events in rats. Major differences in the timing of the developmental sequence between rats and humans include: gonocyte transformation period (rat: postnatal day 0-9; human: includes gestational week 22 to 9 months of age); masculinization programming window (rat: gestational day 15.5-17.5; human: gestational week 9-14); and mini-puberty (rat: 0-6 hr after birth; human: 3-6 months of age). Endocrine disruptors can cause unique lesions in the prenatal and early postnatal testis; therefore, it is important to consider the differences in the timing of the developmental sequence when designing preclinical studies as identification of windows of sensitivity for endocrine disruption or toxicants will aid in interpretation of results and provide clues to a mode of action. Birth Defects Research 110:190-227, 2018. © 2017 Wiley Periodicals, Inc.

The success of new antiretroviral medicines for HIV resulted in a change to guidelines of standard therapy where continuation of antiretroviral therapy is recommended to maintain the low viral load during pregnancy, thereby preventing transmission of the virus to the fetus. As a result, pregnancy related exposure to HIV medicines has increased. Understanding the safety of these medicines during pregnancy is of paramount importance to ensure health of mothers and their offspring; well-designed animal studies that evaluate the reproductive life cycle play a key role in this effort. As part of the medicine development program for dolutegravir (DTG), a series of reproductive and developmental toxicity studies were conducted using rats and rabbits. In a fertility study, where exposure to DTG occurred in female rats before mating through conception and up to implantation of the embryo, no effects on reproductive cycles, ovulation, fertility) or preimplantation embryonic growth were observed. In rat and rabbit embryo-fetal development studies, where exposure to DTG occurred during organogenesis, no malformations or other developmental abnormalities were observed. In a rat pre-and post-natal development study, where DTG exposure to the pups occurred during pregnancy and postnatally via milk, no malformations or other developmental abnormalities were observed. In these studies, no DTG-related effects occurred on fertility, embryonic (pre-and post-implantation loss, resorptions, abortions, and malformations) or fetal development where the multiples of exposure at the maximum recommended human dose were up to 27 times higher in rats or below the human exposure in rabbits.

Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections, and vaccines are needed to treat young children and older adults. One of GSK’s candidate vaccines for RSV contains recombinant RSVPreF3 protein maintained in the prefusion conformation. The differences in immune function of young children and older adults potentially require different vaccine approaches. For young children, anti-RSV immunity can be afforded during the first months of life by vaccinating the pregnant mother during the third trimester with unadjuvanted RSVPreF3, which results in protection of the infant due to the transplacental passage of anti-RSV maternal antibodies. For older adults with a waning immune response, the approach is to adjuvant the RSVPreF3 vaccine with AS01 to elicit a more robust immune response. The local and systemic effects of biweekly intramuscular injections of the RSVPreF3 vaccine (unadjuvanted, adjuvanted with AS01, or coadministered with a diphtheria-tetanus-acellular pertussis vaccine) was tested in a repeated dose toxicity study in rabbits. After three intramuscular doses, the only changes observed were those commonly related to a vaccine-elicited inflammatory reaction. Subsequently, the effects of unadjuvanted RSVPreF3 vaccine on female fertility, embryo-fetal, and postnatal development of offspring were evaluated in rats and rabbits. There were no effects on pregnancy, delivery, lactation, or the pre- and postnatal development of offspring. In conclusion, the RSVPreF3 vaccine was well-tolerated locally and systemically and was not associated with any adverse effects on female reproductive function or on the pre- and postnatal growth and development of offspring.

There was poor correlation between changes in serum levels of Inhibin B and testis histopathology. Based on these observations, the utility of Inhibin B as a hormonal marker for germ cell toxicity is limited.