Maternal tract factors contribute to paternal seminal fluid impact on metabolic phenotype in offspring

Abstract

Paternal characteristics and exposures influence physiology and disease risks in progeny, but the mechanisms are mostly unknown. Seminal fluid, which affects female reproductive tract gene expression as well as sperm survival and integrity, provides one potential pathway. We evaluated in mice the consequences for offspring of ablating the plasma fraction of seminal fluid by surgical excision of the seminal vesicle gland. Conception was substantially impaired and, when pregnancy did occur, placental hypertrophy was evident in late gestation. After birth, the growth trajectory and metabolic parameters of progeny were altered, most profoundly in males, which exhibited obesity, distorted metabolic hormones, reduced glucose tolerance, and hypertension. Altered offspring phenotype was partly attributable to sperm damage and partly to an effect of seminal fluid deficiency on the female tract, because increased adiposity was also evident in adult male progeny when normal two-cell embryos were transferred to females mated with seminal vesicle-excised males. Moreover, embryos developed in female tracts not exposed to seminal plasma were abnormal from the early cleavage stages, but culture in vitro partly alleviated this. Absence of seminal plasma was accompanied by down-regulation of the embryotrophic factors Lif, Csf2, Il6, and Egf and up-regulation of the apoptosis-inducing factor Trail in the oviduct. These findings show that paternal seminal fluid composition affects the growth and health of male offspring, and reveal that its impact on the periconception environment involves not only sperm protection but also indirect effects on preimplantation embryos via oviduct expression of embryotrophic cytokines.T he plasma fraction of seminal fluid contains a complex mix of bioactive proteins and other agents produced by male accessory sex organs, which act after intromission to maximize the chances of successful conception by promoting sperm survival and functional competence (1). Seminal plasma can also affect reproductive events independent of sperm. Seminal fluid regulation of female reproductive physiology is well-known in insects, where effects on female reproductive organs, immune system, and behavioral responses promote fertilization and transmission of the male germ line (2). Rodent, porcine, and human studies show that seminal fluid also exerts a substantial influence on female reproductive tract physiology in vertebrates (3, 4). TGF-β and E-series prostaglandins, produced in the seminal vesicle and other male accessory glands, are major male-female signaling agents in mammalian seminal fluid (5). These factors induce the female reproductive tract to synthesize cytokines and chemokines that in turn influence the immune response to facilitate tolerance of male gametes and the conceptus (3).The periconception phase is a time of developmental plasticity, when the embryo is highly responsive to cues affecting later fetal and postnatal development (6). Greater susceptibility of adult offspring to metabolic disease can res...

Seminal fluid and reproduction: much more than previously thought

“…More recently a direct contribution of the father has been shown to influence the metabolism of offspring. Male rats fed a high fat diet give rise to female offspring with β-cell dysfunction [33], while our own studies provide evidence that male mice devoid of seminal plasma give rise to male offspring with altered metabolic profiles and increased fat accumulation [13].…”

“…In female mice mated to males devoid of seminal plasma expression of embryotrophic factors in the oviduct is reduced while the pro-apoptotic factor Trail is increased. In addition embryos derived from these matings display perturbations in blastocyst formation which can be partially rescued using in vitro culture [13]. A definitive study by Sjoblom et al has demonstrated that addition of GM-CSF into culture media can alleviate some of the detrimental effects of embryo culture on pregnancy outcomes, such as altered placental morphogenesis [47].…”

“…Our own studies have demonstrated the susceptibility to the very early embryo in generating offspring with metabolic perturbations. When in vivo derived 2-cell embryos are transferred to an oviduct not exposed to seminal plasma metabolic phenotypes develop in offspring, whereas in vivo derived blastocyst transferred to the same environment do not [13]. More recently this work has been carried over into the human ART program.…”

“…More recently these studies have been recapitulated in the human, particularly the cervix following intercourse [10][11][12]. Recently we have reported that pregnancies initiated in the absence of seminal plasma in mice give rise to progeny with altered metabolic profiles, obesity and hypertension due in part to perturbations in the peri-conceptional environment and oviduct expression of embryotrophic cytokines [13].…”

Homage to the ‘H’ in developmental origins of health and disease

“…4,[6][7][8][9][10][11][12][13] It is also increasingly becoming apparent that the environmental state of both the mother and father can underpin later diseases in offspring, even those who appear healthy at birth. [14][15][16][17][18][19][20][21][22][23][24][25][26] Such intrinsic and extrinsic factors in animal models and humans include exposure to endocrine disrupting chemicals, such as bisphenol A, phthalates, heavy metals, stress, obesity, high fat/ high caloric diets, metabolic status and starvation conditions to provide a few examples. It is also clear that in general, males may be at greater risk for later disorders, including those of the cardiovascular and neurological systems, than females.…”