Impacts of Maternal Heat Stress on Reproductive Organ Development of Male Mouse Offspring

Abstract Authors: Kimberly Abt¹; Ciro Amato²; Sara Grimm¹; Barbara Nicol¹; Erixberto Olivencia Alvarez¹;

Carlos Guardia¹; Humphrey Yao¹
 

1.    National Institute of the Environmental Health Sciences, Durham NC, United States.

2.    University of Missouri, Columbia MO, United States.

Abstract Text:

The average surface temperature of the earth has been increasing for over 150 years, and 2023 was the warmest year on global record. Increasing global temperatures put the human population at risk of developing comorbidities associated with heat stress, which occurs when the body is unable to regulate its internal temperature. Pregnant women are particularly vulnerable to heat stress as exposure to high temperatures during pregnancy is correlated with increasing prevalence of birth defects of their offspring, such as hypospadias, or incomplete closure of the urethra along the shaft of penis. The causal effects of maternal heat stress on fetal development, particularly of the reproductive organs, remains unknown. In this study, we investigated how increased ambient temperature during the second half of gestation in mice influences development of reproductive organs of the male offspring. Pregnant dams were exposed to 22°C (control) or 38°C (high temperature) for three hours per day, mimicking the situation being outdoor in a hot summer day. The exposure window was from embryonic day (E) 10 to E18, and the embryos were collected at E18 via cesarian section for analyses. We found that such exposure scheme did not affect pregnancy outcomes, including placental weight and size, litter size, sex ratio, weight, and length of embryos.  However, a significant reduction in anogenital distance and increased hypospadias scores were observed in male embryos, both endpoints that are sensitive to testis-derived androgens. We therefore examined the global gene expression of the fetal testis and external genitalia. We found no changes in the expression of genes required for androgen production in the fetal testes between the control and experimental testes. However, significant changes in genes related to stress response was observed in the external genitalia of male embryos exposed to high temperature. These observations implicate that the external genitalia phenotypes observed in mice exposed to high temperature is not caused by testicular defects. Instead, such defects could result from stress response of external genitalia to the heat exposure. Together these data demonstrate that intermittent exposure to high temperature during the second half of the gestation in mice does not adversely affect maintenance of pregnancy, development of the placenta, or size of the fetus. However, exposure to heat stress negatively impacts development of external genitalia in male mice. This is consistent with studies in humans that gestational exposure to high heat correlates with higher incidence of hypospadias, which the rates of such birth defect doubled in the past 50 years. Ultimately, our work highlights the need to investigate how increased temperature, and its associated maternal heat stress affects reproductive organ development, and sheds light on potential causal mechanisms of increased hypospadias in response to heat exposure.