Any species with a harem mating strategy e.g. elephant seals, will benefit from a female skewed sex ratio. Any species which are monogamous will have problems if the sex ratios are not approximately equal e.g. albatrosses.

The growth of a population can be limited through the availability of oocytes through family planning

Thanks Aleksandra for highlighting the harem mating strategy. Indeed there are reproductive strategies that require a female-skewed population to maintain a stable population growth or recruitment pattern, but my concern is on the unnatural factors that result in a skew that is beyond normal. Are there any comments on this?

Hi, Ibrahim. I'd like to say that although i'm particularly interested in non-human species particularly invertebrates, a little more elaboration on your contribution will be great. Come to think of it, this discussion may highlight issues relating to the growth of the human population.

Hi Azubuike,

The first thing that comes to mind following your previous comment is the skew in sex ratios in turtle and crocodile hatchlings in response to increased environmental temperatures. In turtles, higher temperatures during egg incubation lead to the production of more females, but in crocodiles and alligators, increased incubation temperatures lead to more male hatchlings being produced. Given the various environmental warming predictions that have been generated, this could lead to problems for these taxa in the future. Both turtles and crocodilians would likely show numerical responses to any warming scenario, but I think that crocodilians would be the taxa which become oocyte-limited due to the increase in production of male hatchlings.

Thanks Aleksandra for your contribution. And thanks for bringing the discussion to a point where i can pinpoint some issues.

If temperature as an environmental factor can influence sex ratio, are there clear instances that relate the role of polluted environment or habitat quality on the incidence of altered sex ratios or abnormally skewed sex ratios?

Hi Dr. Patil,

Your contribution on sub-cellular mechanisms and the possible role in oocyte quality which in turn may be a limiting factor in population growth is really insightful. Although i'm more interested in the role of epigenetic factors or environmental factors, but i'm sure there should be some relationship environmental factors, sub-cellular depictions and the ultimate manifestation of certain skewed sex-ratios.

Thanks again.

A great example of pollution altering sex ratios in fish is:

Charles R. Tyler and Susan Jobling. 2008. Roach, Sex, and Gender-Bending Chemicals: The Feminization of Wild Fish in English Rivers. BioScience 58(11):1051-1059.

Fishing pressure can also alter the sex ratios of some fish:

Julie P. Hawkins and Callum M. Roberts. 2003. Effects of fishing on sex-changing Caribbean parrotfishes. Biological Conservation 115: 213–226.

In terms of how habitat quality can affect sex ratios:

Heike Pröhl. 2002. Population differences in female resource abundance, adult sex ratio, and male mating success in Dendrobates pumilio. Behavioral Ecology 13 (2): 175-181.

Hope these help!

Thanks alot Aleksandra. 'would be glad if a couple of the mentioned publications could be attached my mail and sent to me. All the same I appreciate your efforts.

Looking forward to other contributions that highlight other dimensions of the question.

And here they are!

And another.........

And the last.

I worked as postdoc in an institute of reproductive health. Being a lb scientist, my work involved rodents mostly. In the labs either wild type or inbred animals are used, the latter to reduce the variability. The former are healthier than the latter and that applies to all species. The inbred strains of rats being used from our colony had a higher fertility rate 40 years ago and were producing litters of 20 on an average. Now the average is only 10 litters!

Diet has improved so this is not due to malnutrition. Neither is it due to environmental conditions because these too have improved, in fact temp is maintained with conditioned air.

Inbreeding appears to be the cause underlying oocyte limitation and smaller litter size. In humans, litter size is voluntarily controlled but not in animals. Sex ratio, I believe has not changed.

Is there an epigenetic cause which affects litter size of inbreds?

Dear Manjeet,

From your write-up it can be inferred that the conditions were 'perfect' for the inbred animals to mate. But one notable challenge of the inbreds is that the gene pool has a narrow set of options, thus limiting the quality and possibly the quantity of offspring .

With regards to the epigenetic scenario i would like to highlight the role of reproductive behaviour in reproductive outcome, the female does not just mate with any male, each species has an inbuilt mechanism for authenticating the fitness of the intended mate. But in captivity the inability to express reproductive behaviour extensively may be reflected in the ability of the species to maximize each mating session to produce the most offspring.

Thanks Aleksandra. I'm very greatful. Cheers.

I am not a vet but I can tell you that reproductive behaviour of many strains of fish and fruit fly has been documented-courtship rituals before they accept a mate from their own species. Hybrid birds and fish have weird behaviour is well documented. In case of lab rodents, because they do not know the difference between wild and captive conditions, perhaps it may not matter. In our animal house, the rodents have a mating room where they are kept, usually in a ratio of 1:4 with their own. They can choose fitness. Partners can be changed and sterile males removed. The timing of mating is fixed for this species and they are allowed to be together till the females are impregnated. The conditions have not changed, if at all, improved bot yet there is a fall in litter sizes(pups/litter). The weak offspring are removed and sacrificed, after pup count. Inbreeding is just not good for fertility even though it serves our purpose of cloning the genes and producing near replicas to minimise variation.

There must be a reason for it.

Victor, the wildlife is on the brink of extinction despite the efforts of Govts. Nature I think does not favour inbreeding. Inbreeding would affecs the growth of the population by compromising on the quality of the oocytes. Maybe many follicles/oocytes gradually become senescent and therefore unfit for fertilization! Point to ponder.

Dear Manjeet, thanks for your comments and contributions.

Although inbreeding has a likelihood of resulting in oocytes that may not be as hardy as those produced in a non-inbreeding population, i dont think the senescent oocyte follicles is a direct effect of inbreeding. A possible explainable mechanism could be linked to the gene pool; inbreeding over a period of time will result in loss of variety of gene products that will reflect in gamete quality, offspring hardiness and ultimately organism survival.

Victor, for a long time I have been wanting to create awareness about the issue of inbreeding. Scientists should think understand the consequences of inbreeding, It is not in the interests of nature. Planet belongs to all species. By limiting choices for outbreeding we are doing a disservice to other species. As you have rightly put it, it will reflect in quality of gametes/oocytes and the survival of the organisms. It is the fittest that will survive in the jungle. I have observed that rodent mothers ate up the weak pups immediately after birth and it was certainly not due to deficiency of calcium as some would have me believe!

Moreover, one can outbreed defective genes whereas inbreeding would fix them in the species forever.In some human populations, inbreeding is a way of life for several reasons- one being property rights and second being established wrong marriage practices prevalent in some cultures. Human populations being large, many do not understand the problems but defective alleles can be inbred to produce homozygosity e.g Diabetes and infertility and many more defects can be inbred. The royals in most cultures tend to be infertile because they intermarry amongst themselves. These days, some are breaking the tradition and marrying commoners which will improve the stock!

Dear Manjeet, I dont think the community of biological scientists are ignorant of this fact; perhaps inbreeding is just a strategy to remove or reduce to the barest minimum all confounding genetic factors.

Victor, being blue blooded does not imply a signature of royalty. Rather it should raise awareness about the ill effects of inbreeding. As I said, it is good for us lab scientists, because inbred animals reduce variation in parameters being tested. Evidently by reducing confounding genetic factors. But it is well understood that animals that are bred for maintaining the purity of their breed viz horses, dogs are immunologically weak and more susceptible to common diseases. I dont think that would improve their chances of survival in the long run. I still maintain that outbreeding is best to get rid of defective alleles from any population and for vigour.

So if we build up a population from a few surviving animals that are on the brink of extinction, we would really not be doing much to expand their population in the long run because these cloned animals would be wiped out by common infections which the wild type usually can withstand.

And what do you mean by reducing confounding genetic factors to a minimum as a survival strategy?

Dear Manjeet, I meant that genetic scientist often want their experiments to be free of confounding genetic factors thus their lab animals are product of inbreeding to ensure this.

....but back to the original question, if some environmental factor like pollution were to affect female species in a way that affects their ability to produce viable oocytes, in what mechanism or process will it affect population growth? This is of great concern particularly when there is an increasing bioavailability of Endocrine Disrupting Compounds (EDC's) in the environment.

Again, it is a good question and yes a matter of concern. At the rate which the people/countries are releasing EDCs in the environment, the oocyte/sperm production is bound to be adversely affected sooner than later. People dont realize what they are doing to the environment, particularly water and soil. EDCs can either mimic natural ligands or block their receptors leading to compromised fertility. Deprivation of hormones and dependent factors can lead to messing up the sex of the feti leading to sterility.In fact, all factors which are likely to be disrupted by endocrine disruptors should be carefully investigated.

My thoughts:

1. First and foremost, look for targets in the PITUITARY gland hormones -secretions which are needed for regulation of fertility.

2. And secondly, look for effects of EDC's in hypothalamic releasing factors and going on to neurotransmitter systems in higher brain centers which regulate these.

3. Thirdly, look for changes in the synthesis, release, and sequestration of gonadal hormones for gonadal steroidal hormone release are involved in the feedback regulation of pituitary hormones at different levels in the brain.Focus on the expression of binding factors/proteins of lipidic gonadal hormones in the brain and gonads.

4. Going on to histopathology of oocytes, taking stock of their numbers in the ovaries, look into the mechanisms of cell division which gives rise to oocytes- pre and post natal.

5. As I said before, senescence of gametes should also be looked at. Alcohol it seems does affect telomeres imlplicated in aging.

5. Lastly, stem cells which give rise to the foetus could also have been affected. Therefore, cell division, longevity and survival processes of gametes need to be looked into. Apoptosis can also occur in cells that are not fit to survive through activation of apoptotic enzymes in order to save injury to the surrounding ovarian tissue.

Victor, here is a direct reply to your question pertaining to the Potential targets of EDCs

my perspective:

1. Primordial or resting follicles, that determine the reproductive potential of a female, are laid down in fetal ovaries and are recruited to folliculogenesis pre-natally. A crucial indicator of this recruitment from resting phase is transformation of granulosa into cuboidal cells indicative of morphological maturity of follicles. Several genes like Oligophrenin 1, ATP6, ant-iproliferative transmembrane protein with TMEFF2 domains, are expressed which rescue the resting follicle and lead to oocyte development. This pathway/signalling process could be dependent upon hormones and targeted by EDCs (Markholt S et al. Global gene analysis of oocytes from early stages in human folliculogenesis shows high expression of novel genes in reproduction. Molecular Human Reproduction. 18(2): 96-110, 2012.

2. Telomeres or DNA sequences located at the ends of chromosomes constitute the biological clock in all the cells. The potential for cellular proliferation is linked to genomic stability and is eventually determined by Telomere length (TL) which shortens with age. Thus TL has been accepted as a marker of biological cellular aging. Alcohol consumption leads to TL shortening. Alcohol seems to depelete pituitary vesicles of reproductive hormones and may be a target of EDCs (Sofia Pavanello1 S et al. Shortened telomeres in individuals with abuse in alcohol consumption. Int J Cancer. 129(4): 983-992, 2011.

3. The supplementation of EGF during in vitro oocyte maturation led to EGF-like peptide expression viz epiregulin, amphiregulin, betacellulin. The addition of 3 EGF-like peptides that act through EGFR in cumulus cells viz epiregulin, amphiregulin, betacellulin, during in vitro maturation of oocytes improved their developmental competence. Epiregulin addition increased blastocyst rates whereas epiregulin and amphiregulin improved blastocyst quality. compared with FSH or EGF. These can be molecular targets of EDCs in vivo (Richani D et al. Mode of oocyte maturation affects EGF-like peptide function and oocyte competence. Mol. Hum. Reprod. 19 (8): 500-509, 2013).

4. Folliculogenesis or development of mature follicles which will ovulate and can be eventually fertilized, requires follicle stimulating hormone. FSH aromatizes thecal testosterone to produce estradiol for development of follicles. Inhibition of aromatization may lead to PCOD like infertility effect. Therefore all these hormones are suitable targets for EDCs. The initial recruitment of primordial follicles and early differentiation occurs independently of gonadotropins and involves ckit ligand (SCF) and nerve growth factor (NGF). Thereafter, follicular growth depends upon FSH and AMH (anti-muellarian hormone/MIS) secreted by the proliferating granulosa cells. Probably, FSH acts to gradually suppress AMH secretion to allow the dominant follicle selection. While peripheral AMH could be restricting recruitment of another cohort of primordial folicles, the levels of AMH in the growing follicles could be responsible for the selection of he ones that will ovulate and fertilize. Serum AMH correlates with number of antral follicles on the one hand. On the other hand, it also regulates the size of primordial follicle pool. AMH is a marker of biological ovarian aging and females become infertile/subfertile if the primordial follicle pool available for recruitment gets exhausted (Christien W et al. Anti-Muellerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Molecular Human Reproduction. 10(2): 77-83, 2004).

Victor 3 more articles in my answer.

Victor 3 more articles mentioned in my reply.

Victor 3 more articles mentioned in my reply. That completes my perspectives.

Dear Manjeet, your response on the mechanisms of actions of EDCs on oocytes was very enlightening. It had given me some food for thought particularly on the molecular aspects, only that your response was not linked to population growth.

On the other hand is it possible that oocytes more vulnerable to EDCs than spermatocytes? perhaps this may explain a bit on the issue of sex ratios.

I will think about it, For some time I was working on tamoxifen-with a view to understanding contraceptive effect of an antiestrogen molecule in the males. It so happens that the drug which acted like an EDC produced a general reversible antifertility effect on the rodent population in terms of litter size. Effect occurred both at pre-implantation as well as post-implantation stages. Loss of embryos was also observed as the resorptions. But the antifertility effect did not skew the sex ratio.

Are you asking whether EDCs can skew this ratio? Or your question is directed at sociological consequences of unnatural loss of females on population?

Victor, I thought about the topic for a while. My views are given below:

Query: How is the growth of a population limited by the availability of oocytes?

Under what circumstances does a female skewed sex-ratio in a population become desirable or detrimental to the local population of a species?

Reply

Rationale: Availability of oocytes in vivo could occur due to various endogenous or exogenous causes which would lead to anovulation, infertility or break in population expansion viz. PCOs, EDCs. PCO syndrome, largely genetic, occurs due to high endogenous androgen levels, and leads to anovulation. EDCs, on the other hand, could mimic endogenous estradiol at the receptors albeit with differences in affinity and would thus have the potential to interfere with the “timely” availability of the natural steroid culminating in anovulation. Estrogenic chemicals in the environment thus have a “potential” target/s in the reproductive axis of female (and male) mammals viz estrogen receptors. Many non structural steroidal analogues are estrogenic because their cognate receptors have an open kind of structure which “accommodates” even non structural analogues. Estradiol levels in vivo change periodically as per the physiological requirements of menarche, estrus cyclicity, pregnancy or meopause. But environmental estrogens neither have the periodicity nor affinity of natural hormone in vivo. The (fat soluble) environmental chemicals tend to accumulate in the biological system, gain access to the natural cognate receptors through systemic route, and compete with endogenous estradiol. Non periodic occupancy of ERs can produce “untimely” activation of non genomic ERβ to produce negative non classical effects. Thus environmental estrogenic chemicals likely modulate biophysical properties of GnRH neurons and perhaps also morphology, to prevent ovulation and estrus cyclicity. However, whereas “anovulation” can limit populations, it would not lead to a “skewed” sex ratio.

Environmental estrogens and Physiology: In my opinion, EDCs could compromise the physiological role of estradiol in vivo. Estradiol of gonadal origin is responsible for both positive feedback which generates the LH “surge” as well as the negative feedback which puts a “break” on the release of GnRH. Hypothalamic GnRH neurons are primarily responsible for the regulation of reproductive functions. GnRH neurons secrete a neurohormone viz gonadotropin releasing hormone (GnRH), the “timing” of which is regulated by “estradiol feedback”. Estradiol produces both “direct” as well as “indirect” effects on GnRH release through ERα/β respectively. Whereas alpha form of receptor is “nuclear” the beta form of receptor is “non genomic”, expressed on the neuronal membrane. Estradiol produces “rapid”, non-classical negative effects to “modulate” the activity of GnRH neurons through ERβ expressed on GnRH neuronal membrane. The “nonclassical” actions of estradiol include modulation of “biophysical” properties of membrane viz. excitability and calcium ion dynamics. ERβ activation leads to phosphorylation of transcription factor CREB (cAMP response element binding protein) via activation of second messenger kinases viz extracellular regulated kinase or ERK1/2 and protein kinaseA/CAMII Kinase. CREB and ERK 1/2 are expressed within GnRH neurons. pCREB is responsible for expressing genes involved in maintaining the “morphology” of GnRH neurons through regulating their spine density critical for “presynaptic” inhibitory “afferent” inputs of GABA interneurons. Anteroventral periventricular, anterior periventricular (AVPV/PeN) and Arcuate nuclei (Arc) GnRH neurons also express KISS1R (kisspeptin) which initiates GnRH release via Gpr54 (G-protein coupled receptor) expressed on GnRH membrane. Kisspeptin synthesis is initiated by estradiol via genomic ERα and is crucial for onset of mammalian puberty, estrous cyclicity and fecundity. The nonclassical actions of estradiol include modulating membrane excitability and calcium ion dynamics. KISS1R neuronal membranes too exhibit a resting membrane potential influenced by KATP channels. The membranes of kiss neurons and GnRH neurons are maintained in a “hyperpolarized” state and prevented from firing. Estradiol shifts their firing pattern to bring about the secretion of GnRH. Whereas estradiol could depolarize GnRH neurons by inducing influx of (positively charged) calcium ions, it could also simultaneously depolarize KISS1R neurons through (positively charged) K ion influx, removing GABAergic presynaptic inhibition mediated via GABAA receptors, causing these to fire. Upstream PKA/CAMII Kinase, presynaptic, second messengers “likely” involved in presynaptic inhibitory “afferents” modulated by estradiol, could be expressed in the “presynaptic” GABA terminals and regulate the trans membrane ionic movements. Simultaneous secretion of KISS1R and GnRH would thus be initiated by systemic gonadal estradiol via genomic and nongenomic ER receptors (Cheong RY et al. Estradiol Acts Directly and Indirectly on Multiple Signaling Pathways to Phosphorylate cAMP-Response Element Binding Protein in GnRH Neurons. Endocrinology 153: 3792–3803, (2012); Kwakowsky A et al. The Role of cAMP Response Element-Binding Protein in Estrogen Negative Feedback Control of Gonadotropin-Releasing Hormone Neurons. The Journal of Neuroscience 32(33):11309-11317 (2012); Kirilov M et al. Dependence of fertility on kisspeptin–Gpr54 signaling at the GnRH neuron. Nature Communications | 4:2492 | DOI: 10.1038/ncomms3492; Seminara SB et al. The GPR54 Gene as a Regulator of Puberty. N Engl J Med 349:1614-27(2003); de Roux N et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. PNAS 100 (19): 10972–10976(2003) ; Fraza˜o R et al. Shift in Kiss1 Cell Activity Requires Estrogen Receptorα. The Journal of Neuroscience. 33(7):2807–2820 (2013).

Skewed sex ratios: Darwin believed that nature does not discriminate and lead to skewed sex ratios. Natural Fisherian sex ratio is 1:1. In human species, the “limitation” in oocytes is manipulated by man for social and economic benefits through reducing the female population through selective abortion of female foetuses, increase in female mortality due to neglect/malnutrition or lack of medical care during pregnancy. Economic reasons have led to undesireable social practices like female foeticide, polyandry, patrilineal inheritance, dowry system, crime against women (rapes), domestic violence, drug abuse, prostitution, trafficking of women, warfare, political instability, spurt in sexually transmitted diseases in Asia (Robert Brook. Asia’s missing women. Evolutionary Psychology(2012); 12(5): 910-925). Limiting the availability of oocytes is desireable in the event of population explosion.

In mideastern societies, polygamy and inbreeding likely became prevalent as a consequence frequent wars, male deaths which skewed sex ratios. Limiting oocyte availability could have become suicidal for the humans, under these circumstances. Increased availability of oocytes in this context is desireable for increasing population for continuation of species even though the risk of inbreeding would also be increased. According to C. Wedekind, skewed sex ratios towards increased numbers of daughters, would increase the population size but decrease genetically effective population size for at least one generation due to inbreeding. In the long run, however, it may correct itself and reduce further loss of genetic variance. (Manipulating sex ratios for conservation: short-term risks and long-term benefits. Animal Conservation (2002); 5:13–20).

So skewed sex ratios, manipulated by man or as a result of natural catastrophes, is not good in general because it can lead to undesireable practices in the human society as a whole. EDCs could also limit the availability of oocytes and this would be undesireable for the survival of human species in the long run. Limiting oocyte availability due to environmental pollutants would ultimately act like a demographic bomb.

In animals, urbanistion and loss of natural habitats, hunting, diseases etc could reduce the population size and this has to be corrected by conservation techniques. Limited availability of oocytes would be detrimental to conservation of animal species.

I do hope that some, if not all, of your query has been answered.

From another point of view, a possible mechanism of ovarian toxicity resulting in unavailability of quality oocytes for successful reproductive outcomes is oxidative stress.

Oxidative stress which arises due to imbalance between prooxidant and antioxidant systems, can result in atrition of ovarian tissue, and possible apoptosis which results in ovarian failure and low reproductive outcomes which ultimately affect population growth.