Prenatal Alcohol Exposure and Pair Feeding Differentially Impact Puberty and Reproductive Development in Female Rats: Role of the Kisspeptin System

Abstract

Background Reproductive maturation is initiated with the onset of puberty, which activates the hypothalamic-pituitary-gonadal axis and coincidences with increased expression of the hormone kisspeptin within the hypothalamus. Maturational events are sensitive to environmental factors, including alcohol, which is known to delay reproductive development. We hypothesized that, similar to alcohol's adverse effects during reproductive maturation, prenatal alcohol exposure (PAE) would alter pubertal markers, sex hormone profiles, and kisspeptin expression in the hypothalamus. Methods Female offspring from control (C), pair-fed (PF), and PAE groups were sacrificed prior to puberty onset (postnatal day [PND] 30), during puberty (PND 35), or in adulthood (PND 65). Estradiol (E2), progesterone (P4), prolactin (PRL) and luteinizing hormone (LH) levels, and Kiss1 mRNA expression were measured in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei of the hypothalamus. Pubertal markers (vaginal opening, uterus/body weight ratio) were assessed. Results Our findings indicate that: 1) PAE inhibits the expected increases in E2 levels with age and delays maturational increases of P4 levels; 2) PAE and pair-feeding have similar adverse effects on: i) vaginal opening and uterus/body weight ratio; 3) Differential relationships between PRL and P4 suggest that different mechanisms may underlie delayed maturation in PAE and PF; that is, PF females have low PRL levels and no increase in P4 with age, whereas PAE animals, despite low PRL, show the expected age-related increase in P4. 4) There is higher mean density of Kiss1 mRNA in the ARC of adult PAE females and altered Kiss1 expression in the AVPV of both PAE and PF females. Conclusions PAE and pair-feeding have some overlapping but important differential effects on hormonal profiles and Kiss1 mRNA expression during reproductive development. Pre-adolescent alterations in Kiss1 expression in the AVPV and ARC, which may change the balance of function in these two nuclei, may differentially contribute to delayed reproductive maturation in PAE and PF compared to C females.

Adverse reproductive outcomes associated with fetal alcohol exposure: a systematic review

“…This ensured that the control group received the same daily caloric intake per body weight as a 'yoked' PAE dam, thus allowing the effects of the liquid diet alone to be disassociated from the specific effects of the EtOH. In some cases, the EtOH was replaced with sucrose (Boggan et al 1979, McGivern & Yellon 1992, 1995, Blanchard & Hannigan 1994 or maltose-dextrin (Udani et al 1985, Esquifino et al 1986, Lan et al 2009, Murugan et al 2013, Sliwowska et al 2016), but in some cases, there was nothing added to substitute for the EtOH (McGivern 1987, Polanco et al 2010, 2011, even though these studies classified their control as 'pair fed'. Chen and Smith (1979) delivered the EtOH in a saccharin solution to treated animals, but controls only received water.…”

“…Interestingly, two studies (Lan et al 2009, Sliwowska et al 2016 reported quite similar hormonal and maturational changes in their PAE and pair-fed offspring Animal studies are ordered based on the timing of alcohol exposure. *Key results are in alcohol-exposed offspring compared to non-exposed, isocaloric (where available) controls; a Tanner stage drawings (Marshall & Tanner 1969) were used to assess breast/pubic hair development in girls; b only adjusted means (no s.d.)…”

“…compared to chow-fed controls, although there were some subtle differential effects. For example, Sliwowska et al (2016) reported that despite both groups having much reduced prolactin (PRL) levels compared to the controls, PAE females still showed the expected agerelated increase in progesterone (P), whereas this was absent in the pair-fed group.…”

“…Although the effects of PAE on the brain were outside the scope of this review, we consider it here as an underlying mechanism for the changes reported in gonadal function. The preclinical study by Sliwowska et al (2016) measured kisspeptin (Kiss1) expression in the hypothalamus and saw changes in PAE offspring that affected reproductive maturation and function. In their earlier study (Sliwowska et al 2014), ovariectomised PAE female offspring, treated exogenously with E2 and P, showed altered responses of kisspeptin/ERα immunoreactive neurons within the hypothalamus, which are involved in the hormonal feedback loops regulating the oestrous cycle.…”

Murine sperm capacitation, oocyte penetration and decondensation following moderate alcohol intake

“…It is widely known that alcohol abuse produces a variety of medical, psycho-sociological and physiological disorders at different levels, including the reproductive system (Canteros et al 1995, Cebral et al 1997, 1998a,b, 2011, Lee et al 2010. Numerous studies have shown the deleterious effects of chronic heavy alcohol consumption on testicular function and spermatogenesis (Shayakhmetova et al 2013(Shayakhmetova et al , 2014, on testosterone serum levels (Salonen et al 1992, Muthusami & Chinnaswamy 2005, Lee et al 2010, Jensen et al 2014, Sliwowska et al 2016) and on hypothalamic-pituitary-testicular axis function (Cicero & Badger 1977, Dees et al 1990, Välimäki et al 1990, Salonen et al 1992, Zhang et al 2005. Clinical manifestations in alcoholic men include hypogonadism, testicular atrophy, feminization, sexual dysfunction (Van Thiel et al 1990, Van Heertum & Rossi 2017, infertility and delayed sexual maturation (Anderson et al 1989).…”